science/technology
AN ORGANIC FEAST Biennial symposium underscores the power of synthetic organic chemistry to create new worlds, drivefundamental discoveries A. Maureen Rouhi C&EN Washington
and just before delivering the award lec ture, Seebach, in a signature gesture, took off his jacket, saying, "I have to work for rganizers of the 36th National Or this award." He described three areas of ganic Chemistry Symposium, held research in his group, all of which require last month at the University of Wis that polymers and oligomersfirsthave to consin, Madison, meant to please the di be prepared. "In the center will always be verse palates of organic chemistry aficio synthesis," he said. nados. The banquet prepared by the Divi No other chemical ac sion of Organic Chemistry of the American tivity could be closer to Chemical Society and symposium execu the heart of Harvard Uni tive director and Wisconsin chemistry versity chemistry profes professor Steven D. Burke did just that sor E. J. Corey, who gave Close to 900 attendees were feted with the symposium'sfirstlec the wide-ranging problems of interest to ture. He expounded on organic chemists through four days of the intricate synthetic lectures and poster sessions featuring challenges continually more than 300 contributions. They also posed by complex natural got the first copies of the new ACS jour products, such as aspidonal Organic Utters. Sessions were held at phytine. This alkaloid is a Wisconsin's historic Memorial Union component of a plantbuilding, by scenic Lake Mendota. based anticockroach pow By tradition, ACS's Roger Adams der that has been used in Corey Award in Organic Chemistry—which in parts of Latin America. cludes a medal, $25,000, and a bound The Corey group's recent total syn volume of the recipient's Chemical Ab thesis of aspidophytine solves one of stracts citations—is presented at this what Corey calls the "classic unsolved symposium. problems" in alkaloid synthesis. And it Dieter Seebach, a professor of organic should help meet another as-yet-unan chemistry at the Swiss Federal Institute swered synthetic challenge, that of hapof Technology (ΕΤΗ), Zurich, received lophytine (structure shown), another al the award this year. After the formalities kaloid in the anticockroach powder that
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appears to be biosynthetically related to aspidophytine (red in structure). Corey acknowledged the contribu tions of Jason D. Altom to the synthesis of aspidophytine, noting that the former Ph.D. student's suicide last year (C&EN, Jan. 25, page 11) was one of those "incomprehensible turns life sometimes takes." A paper describing the syn thesis has been published [/. Am. Chem. Soc, 121, 6771(1999)]. It names Al tom as a coauthor and is dedicated to his memory. The success of com plex syntheses, such as those carried out by the Corey group, is the result of strategy, design, and use of powerful synthetic tools such as catalysts. Three speakers exemplified how the design and prepara tion of new catalysts has become a major activity in organic chemistry. Gregory C. Fu, a chemistry professor at Massachusetts Institute of Technolo gy, described chiral nucleophilic cataly sis based on complexes of planar-chiral heterocycles with transition metals. These complexes are effective chiral catalysts for many processes, including addition of alcohol to ketenes and kinet ic resolution of secondary alcohols. The lecture by Robert H. Grubbs, a chemistry professor at California Insti tute of Technology, highlighted the role of the olefin metathesis reaction as a powerful tool for forming carbon-carbon bonds. Key to expanding the scope of this reaction is the availability of welldefined ruthenium-based catalysts. And Masakatsu Shibasaki, a professor of pharmaceutical sciences at the Univer sity of Tokyo, discussed multifunctional asymmetric catalysts based on heterobimetallic complexes that can function both as Lewis acids and Bransted bases. Like some enzymes, such catalysts accel erate reactions by optimal positioning of JULY 26,1999 C&EN
39
science/technology reactive groups through synergistic cooperation between the two different metals. His group has applied catalysts based on heterobimetallic combinations such as lanthanum-lithium, samariumsodium, and gallium-lithium to reactions for which no catalytic asymmetric methods were available previously. Economic pressures on drug companies to come up with lead compounds within a short time and at a low cost have created a need for more efficient and more productive chemical synthesis. To meet this need, Princeton, NJ.-based Orchid Biocomputer has been developing modular, parallel-processing microreactors based on reusable microfluidic chips, according to Sheila H. DeWitt, the company's senior director for business development. These multilayer, flexible chips are microfabricated for precise fluid management, and they are useful for a broad range of solu-
(Clockwlse from top left): Fu, Shlbasakl, DeWKt, and Grubbs
tion- or solid-phase chemistries at high temperatures. Other speakers discussed assembly-line synthesis with modular enzymes, the catalytic pathway of cytochrome P450, reaction mechanisms from experimental transition states, and peptiderelated research. But the central message is the power of synthesis. In the rest of this report on the symposium, C&EN takes a closer look at research described in Wisconsin that demonstrates this power. The first section offers a view of the world of folding oligomers, a world created through synthesis. The second shows how synthesis efficiently can drive basic discoveries. The third gives a glimpse of the personal side of Seebach, whose achievements in synthesis were honored at the symposium.^
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Amazing Order In The World Of Folding Oligomers
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ynthesis is the essence of organic chemistry, whether the task is to assemble a natural product from scratch, to design a new catalyst, or to invent more efficient ways of executing chemical reactions. And one of synthe sis* most powerful outcomes is the cre ation of previously nonexistent mole cules. New molecules give birth to new worlds unknown in na ture, as well as new tools for probing nature's unknowns. At the 36th National Organic Chemistry Symposium, three views of the new world of unnat ural folding oligomers were pre sented by three of the leading re searchers in the field: Dieter Seebach, a professor of organic chemistry at the Swiss Federal Institute of Technology (ΕΤΗ), Zurich; Samuel H. Gellman, a chemistry professor at the Uni versity of Wisconsin, Madison; and Jeffrey S. Moore, a chemis try professor at the University of Illinois, Urbana-Champaign. Folding oligomers came onto the chemical scene only a few years ago, sprouting in a lot of deferent places. Ifs as if some members of the chemical commu nity were guided by a collective conscious ness to a new set of synthetic targets—un natural molecules that can fold just like the well-folded polymers in nature, such as proteins and RNA, that perform complex
chemical operations. And they can be based on lots of different monomers, as the three lecturers showed. Seebach and Gellman independently discovered that oligomers of β-amino acid residues, called β-peptides, adopt stable secondary structures. Their relatedness to natural proteins and their resis tance to proteases make β-peptides
Gellman (left) and Moore
attractive for therapeutic and biological applications. Moore, on the other hand, has been working with phenylacetylene oligomers with an eye to inventing new materials. Seebach's journey to β-peptides began with the natural polymer polyhydroxybutyrate. The polymer yields i?-3-hydroxybutyrate monomers, which Seebach's group has used as inexpensive chiral
Among secondary structures of oligomers prepared from homologated amino acids that have been discovered are (clockwise from right) helices, hairpins, and parallel sheets.
starting materials for syntheses of enantiomerically pure compounds. Replacing the hydroxyl oxygens in the monomers with nitrogens yields β-aminobutyric acids. In speculating about what might happen if β-amino acids were stitched together into peptides, Seebach recalled that "all the specialists in the world told me that it will result in chaos." Be cause in β-amino acids, the carbon back bone is one carbon atom longer than in regular α-amino acids, many experts thought "adding another carbon-carbon bond will result in a huge increase in the number of possible conformations," he said. But when a coworker prepared the first simple β-peptide, "we saw a 1 spectacular [circular dichroism] | spectrum indicating a secondary I structure in a very short olig| omer," Seebach recalled. It turns £ out that β-peptides, even without | backbone restrictions, can £ form helices, turns, hairpins, parallel and antiparallel pleated sheets, tubes, and meandering structures. "In short," Seebach said, "there is not less structure and or der in β-peptides as predicted, but rather more structural variety." The secondary structures formed by β-peptides also are more stable than those formed by α-peptides. For exam ple, a normal protein helix requires at least 15 α-amino acids, whereas as few as six residues can form a β-peptide helix. Seebach's approach to the world of folding oligomers has been one of discov ery. He and his coworkers synthesize olig omers of homologated amino acids— compounds one or more carbon atoms longer than α-amino acids—observe whether they adopt well-defined conforma tions, and determine what the conforma tions might be. They have begun consider ing γpeptides and arefindingthat these too form stable helices. And they have now established that some of the β-pep tides they have prepared possess biologi cal activity (C&EN, June 28, page 27). Gellman and his coworkers offer a complementary approach by incorporat ing die element of designfromthe start, using computational methods to predict structural features that lead to folding. This approach has led to Gellman's use of fm«s-2-aminocyclohexanecarboxylic acid (ACHC) and fraws-2-aminocyclopentanecarboxylic acid (ACPC) monomers, the small rings of which were designed to re strict theflexibilityof the backbone. JULY 26,1999 C&EN 4 1
science/technology "In our initial work on helical β-peptides, perhaps our most important result was that we could rationally create two very different helical conformations by choosing different types of β-amino acid building blocks," Gellman told C&EN. "Computer simulations led us to the conformation-specifying blocks." The Wisconsin group also is very highly focused on identifying folding pat terns that are stable in aqueous solution. "Folding properties in this solvent are im portant for comparison with conventional peptides in the natural environment, and folding in water is important with regard to medicinal applications," as well as to the creation of oligomers with discrete tertiary structure, just like normal pro teins, Gellman said. Gellman and coworkers have pre pared β-peptides that adopt a helical con formation in aqueous solution (C&EN, March 15, page 13). And their recent analysis of the crystal-packing patterns of β-peptides based on ACHC and ACPC is giving them ideas about how to achieve tertiary structure with β-peptides. For example, in collaboration with
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crystallographer Isabella L. Karle, a researcher at the Labo Fluorescence intensity ratory for the Structure of Mat 12 1 Unfolded ter, Naval Research Laborato 1 10h ry, Washington, D.C., the Wis consin group has analyzed the crystal-packing pattern of a 8h hexamer of (S,S)-trans-ACKC \J. Am. Chem. Soc, 1 2 1 , 6206 6h (1999)]. It shows that the olig & omers align end-to-end to form 4h columns that pack tightly against one another via interdigitation through the cycloFolded hexyl groups. They have ob (CH2CH20)3CH3 served a similar tight packing 20 40 60 80 100 of a hexamer of (R,R)-transVolume % chloroform in acetonitrile ACPC, with interdigitation A phenylacetylene octadecamer assumes a folded through cyclopentyl rings. conformation In the presence of the poor solvent "Tight helix-helix packing is acetonitrile but Is driven to an unfolded conformation In a key feature of the α-helical the good solvent chloroform. Solvent quality refers to bundle tertiary structures com the solvent's ability to solvate the oligomer's backbone. monly found in biological pro teins," Gellman noted. "It may According to well-known principles be possible to harness the cyclohexyl in teractions observed in this crystal to of solvent-polymer interactions, when a create longer β-peptides that adopt heli polymer is in a solvent that poorly sol vates its backbone, the polymer would cal bundle tertiary structures." To go from α-amino acids to β-amino rather be solvated by itself than by the acids "is exciting, but ifs a baby step," solvent. So it will collapse on itself. Gellman told C&EN. "In a sense, you're Thaf s the idea Moore pursued: how to taking the smallest possible step from decorate a backbone with side chains what you know well." On the other that can drag it into a poor solvent so hand, the work of Moore at Illinois rep that it collapses. To achieve amphiphilicity, Moore's resents "an incredible leap of imagina tion," Gellman said. "He uses back oligomers feature a stiff hydrophobic bones that have nothing to do with ei phenylacetylene backbone with side ther protein or RNA. If s a bolder step chains elaborated with hydrophilic ethyl ene oxide groups. Outside of solution, into the unknown." Not only does Moore not use mono the pure oligomers are waxy solids that mers related to proteins, but he also pur organize into lamellar structures \J. Am. posely avoids use of hydrogen bonding to Chem. Soc, 121,5933 (1999)]. Inagood drive oligomers into a stable secondary solvent such as chloroform, they assume structure. His hypothesis is that interac a random conformation. In a poor solvent tions between polymer and solvent are such as acetonitrile, they fold into a puta tive helix, whose twist can be biased by enough to drive specific conformations. The focus of the Seebach and the modifying the backbone \J. Am. Chem. Gellman groups has been "on setting up Soc, 121,2643 and 3114 (1999)]. Moore's world of folding oligomers the kinds of hydrogen bonds that amides engage in," Moore told C&EN. is uncharted territory. On top of the syn thetic work, characterizing the new olig"Our approach is somewhat simpler." It involves building amphiphilicity omers in solution is also a major into the monomer—that is, incorporat challenge. "If you're studying polypeptides, there ing both hydrophobic and hydrophilic groups. "That alone under the right sol are clear spectroscopic signatures for an vent conditions is really going to limit α-helix or a β-sheet," Moore said. "Those the conformational space that the olig have been established for a long time. If omers can explore," Moore suggested. you invent a new backbone, all bets are oft "If the oligomer is properly designed, The pattern that you associate with an weak interactions between the polymer α-helix in a peptide does not apply any segments and the solvent are going to more." Because they can't use the kind of point molecules in the right region of tools that are applied to β-peptides, such conformational space."
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as X-ray and NMR, Moore and his team have had to build, step-by-step, an em pirical body of correlations between structure and various spectra: UV, circu lar dichroism, and fluorescence. Using model compounds, they have systemati cally prepared oligomers of increasing chain length and obtained spectra un der certain solvent conditions. "If you suddenly see something changing, some discontinuity at a particu lar chain length, you know something in teresting is going on," Moore said. "Then you piece everything together." TTie structural predictions were put to test when they modified the oligomers to make the putative helix do something, such as bind a metal. That conformation creates a barrellike structure, which can be made to act like a receptor. Moore and coworkers prepared a dodecamer based on meta-connected phenylacetylene monomers, each attached to a polar triethylene glycol monomethyl ether side chain. Every other aromatic ring contains a cyano group, making six such groups available for coordination. Addition of a metal causes the oligomer to fold into a conformation where the cya no groups fall inside the barrel, creating
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In the solid state, six hexamers of (S,S)-trans-2-amlnocyclohexanecarboxylic acid pack tightly Into columns Interdlgltated through the cyclohexyl groups. The six oligomers are distinguished by the colors of their carbon atoms. All nitrogen atoms are dark blue, and all oxygen atoms are red.
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JULY 26,1999 C&EN
43
science/technology
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coordination sites with high affinity for why you couldn't use this conformation CuOD and Ag(D [Angew. Chem. Int. Ed., al transition to drive gelation," he said. 38,233(1999)]. The fascinating world of folding olig "If the system is really falling into a he omers wouldn't exist without synthesis. lix, the folded conformation should cre "Synthesis is in the center of all this ate trigonal planar coordination environ work," Seebach said. "To obtain results, ments to which metals that prefer trigo one first needs to synthesize com nal planar geometry ought to bind," pounds." The process can be tedious, Moore explained. "Although there's even boring, because the same reac nothing wonderful about binding Cu(I) tions are used over and over. But with and AgQ, it was definitive proof in my out it, the exciting discoveries now be mind that we had a good understanding ing made wouldn't be possible. of the system." The central role of synthesis goes be On the basis that the oligomers his yond folding oligomers. "Putting things to group has prepared aggregate when gether, making new compounds with they are in the folded state, thefirstap new properties, thafs chemistry for me," plication Moore is considering is olig Seebach said. "I'm convinced that in the omers that undergo volumetric phase next century chemists will go more and transitions, similar to polymer gels. "If more into biochemistry, medicine, and bi you could start getting these folded mol ology. If you want to do things in these ar ecules to aggregate, there's no reason eas, you have to be able to synthesize."^
other single-cell organisms. It's unrea sonable to assume that single-cell or ganisms would have optimized com pounds to alter, say, the way the human brain works or any other process in a multicellular organism. To probe any and all biological pro cesses, what is required is a huge collec tion of small-molecule ligands of diverse structures, generated through synthesis that has been tailored to assemble com plex molecules similar to those produced by natural selection. "Thafs where every thing starts," Schreiber said. Both druglike and natural-product-like small molecules are of interest in this col lection. "Druglike molecules typically in hibit enzyme active sites and are opti mized for the concave topography of the active site," Schreiber said. But many pro teins don't have enzyme activity and are involved instead in protein-protein inter actions. "To make molecules that will al ter protein-protein interactions, we turn to natural products," he said. Making natural-product-like mole cules en masse "is a huge challenge for synthesis," Schreiber commented. We've worked very hard on this problem for many years now." The breakthrough they observe the effect. If they do it came last year with a demonstration of enough times to know what genes are what can be done through split-and-pool being mutated, eventually they can de synthesis. Using 18 tetracyclic scaffolds, velop a theory of how some complex 30 terminal alkynes, 62 primary amines, network works. But that approach can 62 carboxylic acids, and a six-step reac be exceedingly slow. tion sequence, Schreiber and coworkers Small molecules also Derek S. Tan, Michael A Foley, and Mat 8 cr can break the circuitry of thew D. Shair prepared more than 2 mil biological systems. For lion distinct chemical entities. the past 15 years, work in In this chemical library, each com Schreiber's lab has fo pound has structural features like those cused on using small found in natural products, and each is molecules—such as nat spatially segregated in a bead, which is si ural products—that alter multaneously encoded during synthesis the function of the pro [/. Am. Chem. Soc, 120, 8565 (1998)]. teins they bind as a com This work "is the equivalent of random plementary way to probe mutagenesis," Schreiber said. "Ifs creat complex biological pro ing circuit breakers." cesses. The approach is At ICCB, researchers Leslie Walling called chemical genetics, and Randall W. King have devised fully and ICCB was founded automated engineering interfaces to dis to develop this new field tribute the synthesis beads into individu (C&EN, Nov. 16,1998, page 31). al wells in a bead arrayer, where the mol But what of proteins for which natu ecules are cleaved from the bead and ral product ligands have not been dis kept in solution. To test the compounds covered or might not exist? And are in whole-cell assays, a portion of each so there enough natural products to ex lution is transferred to arrays of miniature plore any kind of biological process? stock plates, from which arrays of mi Perhaps not, Schreiber said, because cropipets remove nanodroplets of the so many natural products are made by sin lutions and deliver them to miniature asr gle-cell organisms, which have evolved say plates containing arrays of wells, each the compounds through natural selec containing one cell. An imager detects tion for some selective advantage over the light emittedfromeach well.
Using Synthesis To Explain Life's Unsolved Mysteries
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f synthesis is the key that will allow chemists to make a profound differ ence in biochemistry, medicine, and biology, one powerful way to proceed was described at the 36th National Or ganic Chemistry Sympo sium by Stuart L Schreiber, who is a Harvard University chemistry pro fessor, a Howard Hughes Medical Institute investi gator, and a codirector of two interdisciplinary re search centers at Har vard: the Institute of Chemistry & Cell Biology (ICCB) and the Center for Genomics & Proteomics. After devoting the early part of his career to issues of stereoselective Schrelber synthesis, Schreiber be came fascinated with the fundamental problems that biology poses. "If you want to understand something, it's very useful if you can perturb it," Schreiber said. "Complex biological sys tems can be thought of as complex cir cuitry. You need ways to break circuits, turn them on, turn them off, modulate them, in order to understand them." Biologists break circuits through mutations. They induce mutations, and 4 4 JULY 26,1999 C&EN
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That light is the signal that the com pound in the nanodroplet is exerting an effect on the cell in the well. It comes from an assay that uses antibodies to de tect alterations in a biological pathway, a procedure developed by graduate stu dents Brent R. Stockwell and Stephen J. Haggarty. Called the cytoblot assay, it is based on probing whole cells for a par ticular antigen by using a specific prima ry antibody that is linked to a secondary antibody that will emit light when the primary antibody binds to the antigen [Chetn. Biol, 6, 71 (1999)]. Different pathways can be probed as long as there is an antigen whose binding to an anti body can be related to a specific event. The stage is set for large-scale screening. But because of a technical glitch, the 2 million compounds have not yet been screened. In his lecture, Schreiber described how his team in the meantime took an offthe-shelf 16,000-member library of simple synthetic compounds just to check whether the pieces they had assem bled—a collection of compounds, an as say, and robotics for rapid and highthroughput screening—could work as envisioned and discover something new.
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And they asked: Is there any compound here that can help us understand how, during mitosis, cells faithfully segregate the two newly replicated chromosomes perfectly every time they divide? 'The surprise is that we found one," Schreiber said. Mitosis is one of life's fundamental processes that is not yet completely un derstood. 'When a cell divides, it repli cates its DNA. People forget that there's a step right before that: The cell repli cates its centrosome," Schreiber said. The centrosome is a nucleating ele ment for microtubules, also called spin dles, that radiate throughout the cell, giving the cell its shape. It has been speculated that the two centrosomes send microtubules through the nuclear membrane to grab the replicated chro mosomes before they segregate. "No one's really seen" this specula tive stage, Schreiber said. "What you see in textbooks is what happens next: The replicated chromosomes mysteri ously have moved apart. We wanted to know how these things happen." Researchers in the lab of ICCB Codirector Timothy J. Mitchison also have been using the 16,000-member library to
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i
study the problem, but through staining, a powerful but slow technique. Thomas U. Mayer, a postdoc, put cells under a mi croscope and tested the compounds one at a time to see what they do. After four months of doing that, Mayer got through only a fraction of the compounds and found 10 that did something. In Schreiber's lab, Haggarty screened all 16,000 compounds twice in about a week and found 142 that caused a signal in the cytoblot assay. "We went back and looked at the 142," Schreiber said. "Every one caused something weird to happen" at the stage just before chromosome segregation. Compounds that affect chromosome segregation generally do so by disrupt ing the microtubules. They fall into two categories. Some, like vinblastine, dis rupt the microtubules. Others, like Taxol, stabilize them. "Either one is very bad, because microtubules are dynam ic," Schreiber said. "They have to stretch, pull, and segregate." To find out whether the 142 com pounds were affecting microtubulin dy namics, Mitchison took components of tubulin—a- and β-tubulin—and created an equilibrium mixture of the tubes and JULY 26,1999 C&EN 4 5
science/technology free tubulin. To this mixture, he added each of the 142 compounds: 111 had no effect, 30 inhibited microtubule forma tion, and one behaved like Taxol. The Taxol-like molecule, as Schreiber showed during the lecture, consists of two para-substituted aromatic moi eties linked through amide, CHCC13, and amino groups. Schreiber said a communication describing it is being prepared for submission to the Journal of the American Chemical Society. Given the structural simplicity, "I can't resist making a comment about re cent efforts to develop models to synthe size Taxol-like compounds by assessing the structural elements of the natural products that have this property," Schreiber said. "It would be hard to ar gue that any such model could lead to the design of this compound, which emerged from screening." Whether any of the 31 compounds could become drugs is an obvious ques tion, but one Schreiber does not want to answer himself. 'We'll publish these re sults, and I hope someone's interested enough to study them as potential drugs," Schreiber said. "I'm not interest ed in them. Why? Because these mole cules disrupt microtubules, and we al ready have compounds that do that. 'These other 111 are the interesting ones. They disrupt the process, and they don't do it through microtubules. These are the pearls that nature is giv ing us now in the form of synthetic com pounds to illuminate this process." With the slow but powerful cell-stain ing technique, what these 111 were do ing to cells could be seen through a mi croscope. One compound seemed to freeze that speculative stage of mitosis. "It was one of the most beautiful things I've ever seen," Schreiber said. "It's like a supernova of microtubules coming out of some invisible substance in the middle, on the surface of this sphere where all the chromosomes are. Every cell that had this compound looks like that. I couldn't believe it." like the Taxol mimic, this compound has a simple structure, which Schreiber also displayed during his lecture: a phenol substituted at the meta-position with a multisubstituted nitrogen heterocycle. Schrei ber said that they have named the com pound "monoasterol" and that a paper de scribing it has been submitted to Science. Studies have shown that monoaster ol targets a motor protein. This motor protein, called a kinesin-related motor protein, is double-headed, and Mitchi4 6 JULY 26,1999 C&EN
son had speculated that it is exactly the kind of motor that would be needed to push microtubules apart during mitosis. According to Schreiber, Mitchison thought that the supernova effect is what should happen if the compound is targeting such a protein. The chromo somes will no longer be pushed apart. They will collapse and freeze at the tips of the microtubules. 'That was an amazing insight, and it turned out to be dead on," Schreiber said. Mitchison and postdocTarun M. Kapoor took several of the known motor proteins and watched them moving microtubules around. When they added the compound that causes the supernova effect, it didn't
touch any of the motor proteins, except the double-headed one that Mitchison thought could be involved in mitosis. From a haystack of 16,000 simple compounds, a gem has emerged that may lead to a fuller understanding of mi tosis. Other precious nuggets likely will be found among the 2 million naturalproduct-like synthetic products waiting to be screened. Who knows what biological processes they will help to explain? What's clear is that putting synthesis front and center and using it as a discovery engine to drive biological research, as Schreiber is doing, increases the likelihood that life's fundamental questions will be an swered sooner rather than latere
Dieter Seebach: Taking A Magical Mystery Tour
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ne can certainly plan research but not the results." Dieter Seebach likes to make this statement in his writings, his lectures, and even his web site. He addresses it "to all those en gaged in the distribution of research funds," a reminder that research is a pro cess of continuous discovery and learn ing, a mystery tour with wondrous outcomes. Seebach is a professor at the Swiss Federal Institute of Technology (ΕΤΗ), Zurich; one of the world's most cited syn thetic organic chemists, with enormous contributions in reaction mechanisms and synthetic methods; a pioneer in the burgeoning field of folding oligomers; and the latest recipient of the American Chemical Society's Roger Adams Award in Organic Chemistry. The award was presented at the 36th National Organic Chemistry Symposium, held last month at the University of Wisconsin, Madison, where Seebach talked with C&EN. "If I look at the greatest discoveries, all of them have not been really the subject of planned research," Seebach told C&EN. 'They have been found. And I keep telling my students that all they have to do is to be good chemists and be observant. That's the prerequisite for dis coveries. None of the things for which I'm now being awarded have come by sit ting down and thinking very deeply. Dis coveries are made in the lab." Researchers can say what they want to do, but it is impossible for them to
state with certainty what they will dis cover, Seebach said. As an example, he compares two challenges that have been posed to the technological and sci entific communities: putting a man on the moon and finding a cure for cancer. All the technology was there to put a man on the moon when that challenge was posed, Seebach said. "It was just a matter of enough money, effort, people, and it would be done. That was very clear." But a cure for cancer is not yet here, despite years of effort Thafs because the problem is so complicated, and not all the funda mental discoveries have been made. "So you can sit down and say, I want research in the field of cancer. But you can't say, I want a solution in five years. Funding agencies should know that researchers cannot plan the results." Seebach's chemical mystery tour started when he was only 13, with ex periments in his family's home in Karlsruhe, Germany, where he was born. "I made little explosives, did oxi dations and reductions, generated gas es," he recalled. People in a drugstore nearby "gave me things they should never have given to me at my age." At 15, his interest was further fueled by a chemistry teacher in "Gymnasi um," the German equivalent of U.S. high school. But the person who in spired him most was Rudolf Criegee, a chemistry professor at the University of Karlsruhe and under whose guidance Seebach studied for the Ph.D.
Criegee's chemical abilities deeply im pressed Seebach. Among many accom plishments, Criegee discovered the mechanisms of ozonolysis and cleavage by lead tetraacetate, prepared thefirstcyclobutadiene, and laid out the ideas that later led to catalytic enantioselective hydroxylations with osmium tetroxide. "Criegee was one of the best chem ists of the century. Were it not for World War II, I'm sure he would have won a Nobel Prize," Seebach said. Along with his chemi cal gifts, Criegee was also "a very kind person," Seebach recalled. "He demanded performance from coworkers, but he also built very strong hu man relationships that last ed until he died. I visited him again and again, and we became real friends." It was Criegee who defined research as "eine Fahrt ins Blaue," a mys tery tour. "When you in vite a friend to sit in the car and you say let's take 'eine Fahrt ins Blaue/ you're taking this person somewhere without knowing your destination in ad vance," Seebach explained. From mechanistic work with Crie gee, Seebach's chemical mystery tour led him to a postdoctoral stint in the lab of Harvard University chemistry profes sor E. J. Corey, where he developed the dithiane reaction. Sometimes called the Corey-Seebach reaction, it gave See bach the distinction of starting his ca reer with a name reaction. Seebach returned to Karlsruhe for the "Habilitation." Seebach describes this position as being like a second Ph.D. or a driver's license for doing re search that, after three or four years, leads to a "Dozent," the equivalent of an assistant professor position in the U.S. In 1971, at 34, Seebach was named full professor at Justus Liebig Universi ty, Giessen, becoming one of the young est full professors of chemistry ever to be appointed in Germany. In 1977, he succeeded Vladimir Prelog as a profes sor of organic chemistry at ΕΤΗ. Over the years, he advanced organic synthesis through, among others, the principles of "Umpolung" (reversal of re activity), which he applied to many re agents, and the use of chiral compounds from natural sources, notably tartaric acid and 3-hydroxybutyric acid, as inexpensive
Seebach during poster sessions In Wisconsin.
starting materials for syn thesis of enantiomerically pure compounds. Seebach considers his succession to Prelog's po sition as one of those coin cidences showing that re search outcomes cannot be planned. 'The presi dent of ΕΤΗ had decided to eliminate the position after Prelog retired," he said. "They had seven professors of or ganic chemistry at the time, and they said six was enough. But when Prelog got the Nobel Prize, they could not cut his position, and the search for his suc cessor was activated. That's how I got to Zurich and to doing the things I am in this symposium for." Now 62, Seebach faces his own immi nent retirement In 2003, he must relin quish everything at ΕΤΗ to his succes sor, and in the spring of 2000, he will have to stop accepting new Ph.D. students. ETH's mandatory retirement at age 65 "must sound brutal to an American," giv en that in the U.S. researchers can work as long as they can get funding for their ideas. "On the other hand, in the Swiss system, where researchers can run a group of up to 10 people without having to ask for money, it is fair to make room for the young people," Seebach said. "But for an experimental scientist, re tirement is a catastrophe," he contin ued. "What you've done all your life is to have an idea and then go to the lab to test it. You get an answer and then you develop the next idea. Of course when you are 65 and in good shape, the ideas come as they did previously, but you cannot go to the lab anymore."
Retirement promises other magical tours, however. For years, chemistry has monopo lized Seebach's time. "My wife claims it comes before family, before every thing else, and she's probably right. I've been calling myself a piece of fur niture for my wife, because when I'm writing a manuscript or thinking about a problem, I'm there but I don't respond when she talks to me," he said with laughter. "On the other hand, I don't think I could have done what I've done without a family and a wife and a home where I can go and lick my wounds, sometimes." Seebach doesn't think his commit ment to his science is unique. "I think this behavior is typical. If you want to be on top, you have to be totally dedicated. I don't know anybody who has made it who wasn't dedicated like that," he said. "It's like a virus, an illness," he added as an afterthought, smiling. Retirement will allow more time for hobbies Seebach shares with his wife, Ingeborg—reading; collecting fast cars, Bordeaux wines, and German stamps; and sampling the best restaurants in Eu rope. It also will allow more time for the young children in his life. "I have caught myself going home from the lab on a Tuesday afternoon to be with my granddaughter, who is with my wife all day on Tuesdays," Seebach told C&EN. "I have such joy with the lit tle girl—she's almost three years old now. I go shopping with her. I take her to the zoo. Being with her is such an in tensive experience that I forget chemis try for a few hours. Another grandchild is coming soon."^ JULY 26,1999 C&EN
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