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Recipients are HONORED FOR CONTRIBUTIONS of major significance to chemistry THIS IS THE FINAL SET of vignettes of
recipients of awards administered by the American Chemical Society for 2009. A profile of M. Frederick Hawthorne, 2009 Priestley Medalist, is scheduled to appear in the March 23 issue of C&EN along with his award address. Manfred T. Reetz, winner of the Arthur C. Cope Award, and most other national award winners will be honored at an awards ceremony that will be held on Tuesday, March 24, in conjunction with the 237th national meeting in Salt Lake City. The Cope Award recognizes and encourages excellence in organic chemistry; it consists of a medal, a cash prize of $25,000, and an unrestricted research grant of $150,000 to be assigned by the recipient to any university or research institution. Each Cope Scholar Award consists of $5,000, a certificate, and an unrestricted research grant of $40,000. Arthur C. Cope and Arthur C. Cope Scholar Awards are sponsored by the Arthur C. Cope Fund.
ARTHUR C. COPE AWARD One synthetic strategy to manufacture the world’s best-selling drug Lipitor relies on an enzyme that was evolved in a lab to produce an enantiomerically pure chiral building block. The “evolved” nitrilase enzyme is but one example of how Manfred T. Reetz’s pioneering development of directed evolution to do asymmetric synthesis has yielded benefits to scientists and patients worldwide. It also has earned Reetz—currently a director at the Max Planck Institute for Coal Research, in Mülheim, Germany—the 2009 Arthur C. Cope Award, for his “development of a new approach to catalysis, namely the directed evolution of enantioselective and thermostable enzyme.” “Reetz has made a number of truly outstanding contributions to chemical science in many areas, particularly organic synthesis, organometallic chemistry, and homogeneous catalysis,” notes Nobel Laureate Ryoji
Noyori, who is also the president of Wako, Japan-based RIKEN. “However, his most impressive achievement since the 1990s has been a novel approach to asymmetric catalysis, namely the directed evolution of enantioselective enzymes for use as biocatalysts in synthetic organic chemistry. This is truly fundamental and conceptually innovative.” “I’m thrilled to receive the Cope Award,” Reetz says. “It is really a great honor to be among the list of recipients.” Born in 1943 in Hirschberg, Germany, Reetz spent part of his youth in Germany before moving with his family to St. Louis, Reetz Mo., at the age of nine. After completing high school in the U.S., Reetz began studying chemistry at Washington University in St. Louis in 1965. “I wanted since my teenage days to become a chemist, perhaps because my father was an industrial chemist at Monsanto,” Reetz says. He also worked at the company as a part-time student technician in the 1960s, only a few doors away from William S. Knowles, who later received the Nobel Prize—together with Noyori and Barry Sharpless of Scripps Research Institute—in 2001 for asymmetric transition-metal catalysis. Soon after receiving a master’s degree from the University of Michigan, Ann Arbor, Reetz headed back to Germany to complete a Ph.D. in organic chemistry in 1969 at the University of Göttingen, in Germany, under the guidance of the late Ulrich Schöllkopf. This was followed by a postdoctoral stay with Reinhard W. Hoffmann at the University of Marburg, in Germany. After professorship positions at the University of Marburg and the University of Bonn, Reetz was recruited in 1991 to serve as director of the Max Planck Institute for Coal Research, where Karl Ziegler famously
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COURTESY OF MANFRED R EETZ
2009 ACS NATIONAL AWARD WINNERS
developed the catalysts for polymerizing ethylene in the 1950s, ushering in the era of plastics. Reetz says moving to the Max Planck Institute was integral to both the feasibility and success of this award-winning enzyme evolution. Germany’s Max Planck Institutes are called a paradise by some scientists because directors are provided generous operating budgets, excellent facilities, and relatively few grant-writing responsibilities. “We can focus on risky projects,” without the pressure of having to constantly publish and write grants, Reetz explains. The directed-evolution work was one such risky project because it married two very different fields—molecular biology and organic synthesis. The technique also required the development of costly high-throughputscreening analytical apparatus. “Robotic equipment was expensive to buy in the 1990s, and that would have been difficult to do at a university,” notes Reetz. The project had its inception in 1994, when Reetz read about DNA shuffling, a technique for creating new DNA sequences quickly, by Willem P. C. Stemmer of the Affymax Research Institute (Nature 1994, 370, 389). “It inspired me to read more about the emerging field of directed evolution, and I began to speculate that it might be possible to apply Darwinian principles in the laboratory to evolve enantioselective enzymes for use in synthetic organic chemistry,” Reetz recalls. “This required a completely different way of thinking than in the traditional field of asymmetric catalysis based on transition metals.” It took several years of work before the first proof of principle was published in 1997 in Angewantde Chemie International Edition. The paper reported a one-order-ofmagnitude improvement compared with the wild-type enzyme in the selectivity factor for making a chiral carboxylic acid ester using an evolved lipase enzyme. “One of the prime challenges in that early study was the necessity to develop a high-throughput-screening system for evaluating thousands of potentially enantioselective mutants, because such analytical techniques were unknown at the time,” Reetz notes. To do so, Reetz’s team built high-throughput enantiomeric-ex-
Connors. “Of course, I was 19 that year and he was 11,” Reetz adds with a laugh. “The next summer I didn’t have a chance against him.”—SARAH EVERTS
ARTHUR C. COPE SCHOLAR AWARDS Carlos F. Barbas III, was nominated “for
exceptional creativity and pioneering studies in organic chemistry, particularly in the areas of organocatalysis and the application of organic chemistry to chemical biology.” Aldehydic chemistry has been at the core of much of his work. For example, he and his team have made significant advances in the use of unmodified aldehydes as nucleophiles in catalytic asymmetric Michael reactions, according to one colleague. Previously, the direct use of aldehydes as nucleophiles in catalytic asymmetric synthesis had only been accomplished by using enzymes. The unique ability of organocatalysis to provide a means of controlling the reactivity of aldehydes, as developed first by Barbas, has since been widely employed and now provides the basis for numerous novel aldehyde functionalization reactions, the colleague adds. Additionally, Barbas has pioneered a wide variety of catalytic asymmetric multicomponent reactions, including “organo-click” reactions, novel Diels-Alder reactions, and tandem aldol-aldol reactions that led to the first one-pot synthesis of carbohydrates. This work stems from his discovery of the proline-catalyzed intermolecular aldol reaction, which was based on his work in aldolase antibodies. More recently, he has designed novel amino acids that are highly effective anti-Mannich catalysts and has presented a design strategy that allows organocatalysis to work effectively with water as solvent. His pioneering studies now enable the synthesis of each Mannich diastereomer in high enantiomeric excess and provide direction for the conversion of organocatalytic reactions into environmentally benign, water-based reactions. His studies in chemical biology are also notable for their creativity and contributions. Barbas’ studies of the installation of novel enzymatic function in proteins led to the creation of aldoBarbas
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lase antibodies, the most efficient catalytic antibodies yet described and the only “artificial” enzymes that match the efficiency of their natural counterpart. Barbas accomplished this, his nomination letter says, through “creative application of chemical logic” in the design of two generations of mechanism-based haptens. He has gone on to characterize a family of aldolase antibodies from the perspective of their use in synthesis, their immunological formation, and their structure and mechanism. He has also developed novel prodrugs and catalytic strategies for cancer therapy and invented a new class of therapeutic drugs in his development of chemically programmed antibodies. Three chemically programmed antibodies are now in human trials for cancer and diabetes. And Barbas has reported comprehensive studies that now allow creation of proteins capable of binding virtually any DNA sequence and regulating any gene. He has made seminal contributions in catalysis and chemical biology that highlight organic chemistry as a central science. His contributions have decisively enabled advancements in the field of chemical synthesis in general and organocatalysis and chemical biology in particular, the colleague says. Barbas, 44, received a Ph.D. in organic chemistry at Texas A&M University in 1989. He earned B.S. degrees in chemistry and physics at Eckerd College in 1985. He currently holds the Janet & W. Keith Kellogg II Chair as professor in the departments of molecular biology and chemistry at Scripps Research Institute, a post he has held since 1999. Prior to that, he held various junior positions at Scripps Research Institute, following postdocs at the Research Institute of Scripps Clinic and Pennsylvania State University from 1989 to 1991. In 1997, he cofounded Prolifaron, a biotechnology company acquired by Alexion Pharmaceuticals in 2000, and in 2002, he founded CovX, a biotechnology company acquired by Pfizer in 2008. Among his many honors, Barbas is the recipient of the 2009 Tetrahedron Young Investigator Award.— COURTESY OF CARLOS BARBAS
cess screens based on mass spectrometry, circular dichroism, and even infrared cameras measuring heat evolution. Reetz and his colleagues then went on to direct the evolution of mono-oxygenases, so that they produce chiral ketones and lactones with enantiomeric excesses unrivaled by synthetic catalysts. “This pioneering work by Reetz had an enormous technological impact. Many other academic and industrial groups worldwide were inspired to apply these strategies in the directed evolution of other enantioselective enzymes,” Noyori says. These days, Reetz is concentrating on developing methodology to make directed evolution faster and more efficient. In particular he has developed Iterative Saturation Mutagenesis to quickly produce highquality DNA mutation libraries that are the essential gear for directed-evolution laboratories. The technique is also economical because it “drastically reduces the size of the libraries and thus the necessary molecular biological work, as well as the screening effort, while providing much better mutants,” Noyori notes. Reetz also recently has been making inroads into applying directed evolution to the production of “hybrid catalysts,” which are enzymes with anchored synthetic transition metals or ligands. His lab recently evolved enzymes that can perform Rh-catalyzed asymmetric olefin hydrogenation. “The depth and breadth of Reetz’s knowledge, together with his creative instincts, have enabled him to make key contributions across nearly the entire range of our field,” Sharpless says. These include, “for example, new synthetic methods, asymmetric reagents and catalysts, creation of an ingenious method for rapid screening of homo- or heterogeneous catalysts via heat evolution with an infrared camera, and mechanistic insights into crucial reactivity issues involving both experiment and theory.” To get the inspiration for the experiments reported in his more than 450 publications, Reetz likes to either sit alone in a silent room or “go to the lab to kick around ideas with my creative coworkers,” an activity he finds very rewarding, he says. Reetz is a father to four children and enjoys listening to classical music with his wife. He is also a big fan of tennis, a game he used to play avidly. In fact, while working as a court attendant at Washington University in St. Louis in his early college days, Reetz recalls, he regularly beat eight-time Grand Slam champion Jimmy
PATRICIA SHORT
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Victor J. Hruby decided to pursue a career
in science instead of philosophy because he is passionately interested in how chemical structure relates to biological properties. Colleagues say he started doing chemical biology about 40 years ago—well before the field had a name. Hruby is a Regents Professor Emeritus of Chemistry at the University of Arizona, Tucson. He joined the faculty in 1968 and currently holds departmental appointments in chemistry, biochemistry, molecular biophysics, medical pharmacology, and neuroscience, as well as at the Arizona Research Laboratories. He is being honored for his groundbreaking contributions in organic chemistry related to design, synthesis, and evaluation of conformationally constrained amino acids and their Hruby
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incorporation into biologically relevant peptides. He first became acquainted with chemical structures at the University of North Dakota, where he received a B.S. in chemistry and mathematics in 1960 and an M.S. in chemistry in 1962. In 1965, he completed a Ph.D. in organic chemistry at Cornell University. Because he wanted to learn more biochemistry, he did a stint as an instructor in Cornell’s medical school. Hruby recalls that his work in chemical biology began at the medical school and started to flourish during his subsequent postdoc back in the chemistry department at Cornell. He learned how to solve the structures of floppy hormones such as oxytocin with nuclear magnetic resonance— then a new technique. He also made new molecules that couldn’t be crystallized for analysis by X-ray methods. The only other method to get the structure was NMR, so he learned quickly. “Hruby was one of the first to appreciate that NMR methods could provide conformational information that would enable the peptide chemist to understand the relationships between primary structure and biological activity,” according to a colleague. Hruby also designed and synthesized nickel complexes for asymmetric synthesis that yielded some of the first substituted and constrained amino acids via Michael addition reactions and alkylation reactions. “Since the early 1970s, Hruby has been interested in how one could utilize synthetic and physical organic chemistry to address significant biophysical questions,” says Indraneel Ghosh, an associate professor of chemistry at the University of Arizona. Hruby has helped to develop synthetic hormones and neurotransmitters with high potency, prolonged activity, high receptor selectivity, and stability against proteolytic breakdown. Along with biological collaborators, he has designed compounds related to melanotropins, endocrine chemicals that affect a wide variety of physiology and behavior such as pain and addiction, obesity and anorexia, sexual dysfunction, learning, and hormonal responses from childbirth to maternal behavior. Two compounds related to skin pigmentation dysfunction and cancer prevention are currently in clinical trials. COURT ESY O F VICTOR H RUBY
under mild conditions. His group has discovered a zirconium compound that, at room temperature, combines nitrogen and hydrogen and ultimately releases free ammonia when heated. “Well before the current media fervor about resource conservation and economic sustainability, Chirik’s group was focused on the challenge of improving nitrogen fixation—a chemical transformation whose current energy requirements render crop fermentation products such as ethanol too energetically expensive to serve as alternatives to fossil fuels,” a colleague says. Chirik’s research has led him to publish more than 50 papers in the past six years and receive a range of professional accolades, including being named a David & Lucille Packard Fellow in Science and Engineering, and a Cottrell Scholar and being given a National Science Foundation Career Award in 2003. He has also been recognized for his devotion to turning others on to the magic of chemistry: He was named the Camille Dreyfus Teacher Scholar in 2006, and he received the Stephen & Margery Russell Distinguished Teaching Award in 2005.—LISA JARVIS COURTESY OF PAUL CHIRIK
Inspiration strikes in many forms, and in the case of Paul J. Chirik, the Peter J. W. Debye Professor of Chemistry at Cornell University, some might say the most notable research in his young career was a product of pure thriftiness. Chirik, 35, has designed a class of iron compounds that could be inexpensive and environmentally friendlier alternatives to the catalysts used in a range of industrial processes. “The joke around here is that I was too cheap to buy rhodium,” Chirik says. He thought it would be a cool trick to mimic more expensive metals like iridium and rhodium by using iron. “It was an interesting chemical problem that also had potential practical significance,” he adds. Chirik’s lab has figured out how to store electrons in the ligands of iron compounds and then coax a reversible transfer of the electrons between the ligand and metal. The electronic structure of the resulting Chirik class of reduced bis(imino) pyridine iron compounds could prove extremely useful in olefin hydrogenation and hydrosilylation. “Chirik’s iron catalysts exhibit activities and selectivities that rival traditional rhodium compounds and thus represent a major breakthrough in the field that has attracted interest from major commodity and specialty chemical firms,” a colleague notes. Chirik first got interested in organometallic chemistry as a freshman at Virginia Polytechnic Institute & State University, when chemistry professor Joseph S. Merola took him into his lab. Chirik had been waffling between chemistry and history as his major, but Merola sat down with the student almost daily to discuss data, and soon Chirik was hooked. As an undergraduate, he studied organometallic catalysis in water at a time when conventional wisdom dictated those reactions had to be done in a dry-box. As a graduate student at California Institute of Technology, he shifted his focus to polymerization catalysis, where his work to make petroleum feedstock more efficient predated the current swell of interest in energy conservation. Today, in addition to his work on iron catalysts, Chirik is exploring ways to exploit readily available atmospheric nitrogen to generate more valuable products
Colleagues describe the mechanistic work of William D. Jones in organometallic chemistry as exceptional, insightful, and pathbreaking. “He is one of the leading organometallic chemists of his generation, and his research involves originality in experimental design, elegance in execution, and deep insights into data analysis,” says Charles P. Casey, the Homer B. Adkins Emeritus Professor of chemistry at the University of Wisconsin, Madison. “He has addressed problems of enormous significance, and his penetrating analysis and the deep insights gained from these studies have taught us not only new concepts and new ways to think about bond activations, but also new ways to mechanistically dissect such problems,” claims Maurice S. Brookhart, the W. R. Kenan Jr. Professor of Chemistry at the University of North Carolina, Chapel Hill. Jones’s work concentrates on the coordination Jones and oxidative cleavage of carbon-hydrogen bonds of simple hydrocarbons to transition-metal centers, especially rhodium complexes. His many discoveries in this area include the first direct information about competitive hydrocarbon activation and the fact that alkane activation competes kinetically with arene activation even though the latter is favored thermodynamically. Another goal Jones, 55, has pursued is carbon-hydrogen bond functionalization. His success with complexes containing functionalized ligands such as isocyanides,
demonstrates that catalysis is possible under the proper conditions. In related work, Jones has found a metal complex that can be used for intramolecular functionalization of sp3- and sp2-hybridized C–H bonds leading to catalytic syntheses of indoles, quinolines, and isoquinolines. Jones is also being recognized for his mechanistic talent and insights to key problems involving metal-mediated cleavage of other strong carbon bonds, including carbon-sulfur, carbon-fluorine, and carboncarbon bonds. In one case, he developed an active nickel hydride dimer that removes the sulfur from dibenzothiophene and is regenerated afterward. “This work has the potential to lead to new, efficient desulfurization catalysis, a potentially important advance in environmental chemistry,” Brookhart says. Jones also has made advances in the development of methods for studing aryl–CN bond cleavage and aryl-acetylene cleavage. “Jones has extended his studies to include a detailed understanding of C–CN cleavage in the DuPont adiponitrile synthesis, in which allyl-cyanide C–CN bonds are reversibly cleaved and formed,” Casey says. “His articles demonstrate not only exceptional experimental abilities, but also keen insights broadly applicable across organo-transition-metal chemistry and into other fields, including physical organic chemistry,” comments John E. Bercaw, the Centennial Professor of Chemistry at California Institute of Technology. Jones received a B.S. in chemistry from Massachusetts Institute of Technology in 1975 and a Ph.D. from Caltech in 1979. After a one-year position as a National Science Foundation postdoctoral researcher in Casey’s lab, Jones joined the faculty of the University of Rochester, where he currently is the C. F. Houghton Professor of Chemistry. Among the numerous honors Jones has received during his career are the 2003 ACS Award in Organometallic Chemistry. He is also the recipient of a John Simon Guggenheim Fellowship, a Fulbright-Hays Scholarship, a Royal Society Guest Research Fellowship, and the Fellowship Award from the Japan Society for the Promotion of Science. Jones serves as an associate editor for COURTESY OF WILLIAM JONES
Hruby has been integrally involved in using organic chemistry to dissect human biology and is a true pioneer in a field that is now called chemical biology, Ghosh adds. Among Hruby’s awards are the ACS Ralph F. Hirschmann Award in Peptide Chemistry and China’s Cathay Award, both received in 2002. Despite his scientific achievements, Hruby has not forgotten about philosophy and art. He combined his interests in science and philosophy by teaching a course called “Scientific and Ethical Aspects of Modifying Human Behavior.” An avid patron of the arts, he often attends ballets, theater performances, and music concerts.—RACHEL PETKEWICH
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the Journal of the American Society.—DAVID HANSON
As a pioneer in the field of engineered biosynthesis, Chaitan Khosla—a chemical engineer at Stanford University—might seem like an unconventional choice for an Arthur C. Cope Scholar Award, which was established to recognize and encourage excellence in the area of organic chemistry. But Khosla’s recognition demonstrates organic chemistry’s breadth, as well as the similarities all chemists face when they set out to construct a complex natural product, whether they’re building it in a round-bottom flask or assembling it with an enzyme, as Khosla does. “I see what we do as being very much analogous to the way many of my synthetic colleagues see what they do,” Khosla says. “A synthetic chemist thinks about the discovery of new chemistry, the mechanistic analysis of the fundamental principles that underlie that new chemistry, and the translation of this new chemistry into practical applications for making materials that couldn’t have been made before or making materials that could have been made before with much greater difficulty in easier ways. “Those three themes—discovery of new chemistry, understanding the mechanistic principles, and application of new chemistry—are the three pillars of our research programs,” he continues. “We seek to discover new chemistry that exists in nature. We seek to understand the mechanistic underpinnings of that chemistry, and we seek to exploit that chemistry to practical ends. Conceptually you’re doing the same things, you’re trying to understand how bonds are made and broken and what’s in it for the person on the street.” Currently, Khosla, 44, is the Wells H. Rauser & Harold M. Petiprin Professor of Engineering. He says his interest in nature’s superior synthetic strategies for making polyketides was first piqued in his final years as a graduate student at California Institute of Technology. Enzymes and biocatalysts were once thought of as highly specialized systems, he explains. But by the early 1990s, he says, “it was becoming clear that the mega synthases that make complex antibiotics were very unusual in the sense that they were modular catalysts. You could think of them as the equivalent of the assembly lines for chemical catalysis.” He has spent his career trying to understand how this biological machinery works and how it can be made to make
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Mohammad (Mo) Movassaghi doesn’t just
remember the course that inspired him to choose a career in organic chemistry; he even recalls the molecule that first piqued his curiosity. Although he always knew he intended to pursue the study of science, Movassaghi says that his second semester
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to achieve structural complexity in highly creative ways.” Many of the alkaloid syntheses to come out of Movassaghi’s group, Jacobsen says, “are breathtakingly efficient and elegant. These are targets that have been addressed by some of the great minds in synthetic organic chemistry over the years, but Movassaghi’s syntheses are dramatically shorter and more impressive.” Movasssaghi’s methodology research is equally impressive, notes his MIT colleague Stephen L. Buchwald. Movassaghi has developed methodology for preparing highly substituted pyridines, pyrimidines, quinolines, quinazolines, and related heterocycles. “Not only is this a ‘wow’ reaction,” Buchwald points out, “but it is particularly novel that it can utilize the double bond of an aromatic group as if it were simply the C=C bond of an alkene.” Movassaghi’s other methodology projects include the invention of a formal [3+3] cycloaddition of in situ-formed enamines with cycloalkenones. “What we’re excited about is being able to create molecular complexity as rapidly as possible and with as much use of the inherent chemistry of reactive intermediates,” Movassaghi says. “In many ways what we do is try to predict as well as we can what possible intermediates could be in the biosynthetic pathways leading to these really beautiful molecules.” When Movassaghi isn’t pursuing chemical challenges, chances are good he’s pursuing athletic ones. He’s an avid tennis player and often runs with his wife, MIT chemistry professor Sarah E. O’Connor. “She’s an outstanding scientist and an inspiration to me,” he says. “It’s demoralizing running with her,” he adds playfully. “She’s a very good runner, and when you run uphill, she just takes off. Every time that happens, it reminds me of how she tackles difficult problems. The more difficult the problem, the more she pushes.” That sort of tenacity is something Movassaghi says he tries to emulate as well as encourage in his students when they face tough chemical hurdles. “Once you’ve identified a problem, do everything possible to address the question you’re interested in,” he advises. “Don’t hold back.”—BETHANY COURTESY OF MOHAMMAD MOVASSAGHI
BETHANY HALFORD
of undergraduate organic chemistry at the University of California, Berkeley, truly sparked his interest in the field, specifically the lecture on the chemotherapeutic agent mitomycin C. “Here was this beautiful small molecule that had such powerful reactivity associated with it,” Movassaghi says. “It had the ability to cleave a DNA strand with this very elegant chemistry, and that highlighted for me the power of small organic molecules.” Since that illuminating lecture, Movassaghi has had an impressive career in organic synthesis. He began by doing undergraduate research with Paul A. Bartlett at UC Berkeley. Graduate work with Andrew G. Myers followed, first at California Institute of Technology, and later at Harvard University. He continued his postdoctoral studies at Harvard with Eric N. Jacobsen as a Damon Runyon postdoctoral fellow. Movassaghi then moved to the other side of Cambridge to take an academic position at Massachusetts Institute of Technology, where he’s currently an associate professor. Movassaghi’s dual research focus in total synthesis and the development of synthetic methodology is being honored with an Arthur C. Cope Scholar Award “for his creative syntheses of biologically interesting alkaloids and for the development of new and general routes to nitrogencontaining heterocycles.” “Mo has described beautiful syntheses of highly complex alkaloids such as (–)-calycanthine, (+)-chimoanthine, and (+)-folicanthine, the galbulimima and myrmicarin alkaloids, and the nonalkaloid illudin natural products, important agents in advanced trials for human cancer therapy,” Myers notes. “These works are characterized by a striking degree of imagination and inventiveness with regard to synthetic approach and for the novelty of the chemistry employed in their execution.” Jacobsen adds that Movassaghi’s work demonstrates “an extraordinary sense about how to incorporate biomimetic strategies Movassaghi COURTESY OF CHAITAN KHOSLA
molecules. In doing so he’s garnered an Arthur C. Cope Scholar Award “for his seminal contributions to understanding the mechanisms of polyketide biosynthesis and for the use of engineered biosynthesis for the production of new polyketides and therapeutic leads.” “Khosla has had a profound impact in chemistry, pioneering the emergence of the field of engineered biosynthesis and its application to the practical synthesis of natural and nonnatural products, including many drugs, therapeutic leads, and biological probes,” says Paul A. Wender, Khosla’s colleague at Stanford. “He has advanced our understanding of how nature’s biosynthetic machinery can be engineered to synthesize natural and nonnatural products. This had changed how we think about many areas of synthesis and has equipped the modern synthetic chemKhosla ist with a powerful and general tool to prepare therapeutic leads, materials, and novel structures.” Over the course of his career, Khosla has authored more than 230 papers. He holds more than 50 patents and is the founder of two biotech companies, Kosan Biosciences and Alvine Pharmaceuticals. “He has enabled the synthesis of more natural products than many make in a career and, in addition, has shown that by understanding the mechanisms of the biosynthesis machinery, one can assemble unnatural products with exceptional facility,” Wender adds. Although he has received numerous awards and achievements, Khosla says that he is proudest of his students. “They are the reason why I do what I do,” he tells C&EN. “I’ve been blessed with many amazing students and I consider it a deep privilege to have a chance to engage them when they’re at the beginning of their chemistry education and ride that wave with them as they go through and become world leaders.”—
HALFORD
Pharmaceutical companies licensed this method to synthesize substituted amino acids and other molecules. Prakash explains that Petasis’ long-term collaboration with biomedical researchers has led to a stream of breakthroughs in understanding lipid mediators, molecules that control physiological processes such as inflammation. He adds that these breakthroughs resulted in a paradigm shift on how to control inflammation. Two compounds that Petasis initially synthesized have led to new anti-inflammatory drug candidates now in clinical trials. The work has triggered new collaborations to investigate treatments for several diseases, including periodontitis and cystic fibrosis. Recently, the work of Petasis and his collaborators established the first potential mechanisms for the health benefits of omega-3 fatty acids, which led to new therapeutic agents now in development for treating inflammation. “As indicated by his success in several diverse areas, ranging from new synthetic methodology to synthesizing bioactive materials, Petasis has demonstrated an uncommon versatility and breadth,” says K. C. Nicolaou, a chemistry professor at Scripps Research Institute who was Petasis’ Ph.D. adviser. Born in Cyprus, Petasis completed a B.Sc. in chemistry at Aristotle University of Thessaloniki, in Greece, where, as a college junior he penned a 500-page organic chemistry textbook in Porco Greek. At the University of Pennsylvania, he completed a Ph.D. in organic chemistry and was an adjunct faculty member for two years before joining the faculty at USC.—RACHEL PETKEWICH Colleagues of John A. Porco Jr. single him out as a “highly accomplished designer and conductor of the total synthesis of complex, biologically relevant molecules,” as well as for his “uncanny ability to bring out the best in everyone he touches.” Porco, 45, received a Ph.D. from Harvard
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University in 1992. He went on to do postdoctoral work at Scripps Research Institute before joining the venture capital firm Avalon Technologies in 1993. The venture capital work to develop companies was an interesting way to apply his science skills, he says. But the bench called him back, and in 1995 he helped form Argonaut Technologies to develop instrumentation for parallel synthesis. Porco’s passion, however, is natural product synthesis, and in 1999 he joined the Boston University chemistry department to pursue a research program in that area. Since then he and his colleagues have synthesized more than 25 complex natural products. One compound of particular note is (+)-hexacyclinol, an antiproliferative metabolite that had been isolated from a fungus in 2002 and was the subject of some controversy over its structure (C&EN, July 31, 2006, page 11). Porco and colleagues designed a synthesis around a highly stereoselective Diels-Alder dimerization of an epoxyquinol monomer, followed by an intramolecular acid-catalyzed cyclization (Angew. Chem. Int. Ed. 2006, 45, 5790). When the resulting compound had a 1H NMR spectrum that matched that of the original isolate, the structural debate was put to rest. At the same time as the hexacylinol work, Porco was also working on the total synthesis of (–)-kinamycin C, one of a family of diazobenzofluorene antibiotics that were first isolated in 1970. Porco and graduate student Xiaoguang Lei accomplished the synthesis through an asymmetric nucleophilic epoxidation to establish the correct stereochemistry of the compound’s highly oxygenated D ring (J. Am. Chem. Soc. 2006, 128, 14790). They also took the approach of installing a highly reactive diazo group very late in the synthesis. Porco is now working on synthetic strategies that involve dearomatization—using flat, aromatic rings as scaffolds before removing the aromaticity to form a more complex structure. Porco also turns to biosynthesis for inspiration when grappling with new synthetic methods to prepare elusive natural products and analogs. Complementing his work on natural product synthesis, Porco spearheaded the COURTESY OF JOHN PORCO JR.
chemist rather than a medical doctor because he thought he could help more people by making discoveries that lead to treatments for diseases. His findings have helped develop a drug that alleviates side effects of cancer therapy and other compounds currently in clinical trials. Petasis, 54, is the Harold E. & Lillian M. Moulton Professor of Chemistry at the University of Southern California. Colleagues praise him for his discovery and development of new organic reactions, particularly involving titanium and boron compounds, and for advancing the chemistry and biology of molecules that shut down inflammaPetasis tion and promote healing. “His work is often characterized not only by originality, but also by an underlying simplicity, practicality, and usefulness,” says G. K. Surya Prakash, a chemistry professor at USC. Petasis has introduced three unique chemical reactions that bear his name and are highly effective under mild conditions, Prakash adds. The Petasis olefination uses dialkyl titanocenes to convert carbonyl compounds to their corresponding olefins. Dimethyl titanocene is now referred to as the Petasis reagent. Merck licensed the process for the initial multi-hundred-kilogram scale-up of a drug candidate that became the recently marketed Emend, a drug that can help prevent nausea and vomiting caused by chemotherapy. Petasis’ group later extended the olefination chemistry to include the synthesis of substituted olefins, allenes, and many carbocyclic and heterocyclic molecules. The Petasis-Ferrier rearrangement, an aluminum-mediated reaction, allows stereochemically controlled synthesis of cyclic ethers. Colleagues say that the rearrangement has been helpful in synthesizing complex natural products. Drug companies also took a shine to the Petasis reaction, a boron-based multicomponent reaction that can be used to prepare in one step a wide range of molecules with potential therapeutic value. Amines and carbonyls are treated with a “matchmaker” boronic acid derivative to directly generate highly functionalized nitrogen-containing products. “Without all three being present, there is little or no reaction,” Petasis says.
COURTESY OF NICOS PETASIS
Nicos A. Petasis decided to become a
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“Moving from the organic chemistry lab of Gilbert Stork at Columbia University to a postdoctoral fellowship in molecular biology was quite unusual in 1982,” admits David H. Sherman, 51, the Hans W. Vahlteich Professor of Medicinal Chemistry in the College of Pharmacy at the University of Michigan, Ann Arbor. However, Sherman’s penchant for forging new paths has served him well. The bacterial genetics training he gained as a National Institutes of Health postdoctoral fellow at Massachusetts Institute of Technology allowed him to pursue his passion for investigating the genetic and biochemical basis of microbial biosynthesis Sherman of natural products. While serving in various academic and industrial positions over the past 18 years, Sherman has conducted groundbreaking research in this area, studying terrestrial and marine organisms such as actinomycetes, cyanobacteria, and fungi. Sherman is “fearless in his ability to approach problems from a diverse viewpoint,
and his multidisciplinary efforts typically coalesce into a rigorous and elegant evaluation of exciting research problems at the forefront of organic chemistry,” according to John Montgomery, a fellow chemistry professor at the University of Michigan. Sherman developed a love for natural products as an undergraduate working with Phil Crews at the University of California, Santa Cruz. As his Ph.D. adviser, Stork then instilled “a wonder and a curiosity for molecular architecture,” he says. “Those influences provided the foundation for my long-term research interests.” Along with a team with broad expertise in enzymology, molecular genetics, metabolic engineering, and organic synthesis, Sherman has focused on characterization of genes and enzymes involved in natural product assembly, tailoring, and mechanisms of antibiotic-resistance, Montgomery notes. In particular, Sherman’s study of the methymycin/pikromycin biosynthetic system “highlights the range of investigations that his laboratory has pursued over a multiyear period to provide insights into polyketide chain elongation, processing, termination, cyclization, and tailoring,” Montgomery adds. Initially, Sherman was drawn to this macrolide pathway because of its unique ability to produce both 12- and 14-membered macrolactones as well as its unusual number of hydroxylated forms. More recently, Sherman and his group developed an efficient way to assemble cryptophycin anticancer drugs by using a combination of chemical and enzymatic methods. As a final step, they employ the CrpE cytochrome P450 to stereospecifically install the -epoxide that is key to the cryptophycins’ biological activity. “This solved a longstanding problem that we hope will provide greater, more affordable access to these important molecules,” Sherman says. Sherman is working with Ann Arbor-based Alluvium Biosciences to commercialize the method for creating new cryptophycin analogs with enhanced anticancer properties. Sherman has also completed detailed studies of curacin A biosynthesis from the marine cyanobacterium Lyngbya majuscula. Discovering a new mode of chain initiation COURTESY O F DAVID SHERMAN
establishment and is now director of the Boston University Chemical Methodology & Library Development Center (CMLDBU), a National Institutes of Health Center of Excellence. One current project involves high-throughput screening to identify new chemical reactions that might be useful for synthesis (J. Am. Chem. Soc. 2007, 129, 1413). Porco is one of the leaders of natural products synthesis, says Samuel J. Danishefsky, a professor of chemistry at Columbia University and the director of the Laboratory for Bioorganic Chemistry at Memorial Sloan-Kettering Cancer Center, in New York City. He praises Porco’s “ability to orchestrate the assembly of complex target systems.” And although Danishefsky is not typically a fan of chemical libraries, he nonetheless commends Porco’s work at CMLD-BU for “practicing high standards of chemical synthesis and producing pure compounds in reasonable amounts.” John K. Snyder, one of Porco’s colleagues in the chemistry department at BU, adds that Porco “can build a team of researchers and keep it running smoothly, something not always very easy with the different personalities that exist within a department.”—JYLLIAN KEMSLEY
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in curacin A biosynthesis was particularly gratifying, he says. It involved “a totally unprecedented mechanism and required challenging biochemical, bioanalytical, and structural biology approaches to dissect the details,” he says. “However, once it was completed we could sit back and appreciate the beauty of this new process and its widespread application in natural product systems.” For the long-term, Sherman hopes to harness the biochemical tools provided by secondary metabolic pathways to build entirely new natural product core structures with diverse biological activities and other high-value properties. As a recipient of the Arthur C. Cope Scholar Award, Sherman says he is “especially pleased that ACS has recognized this important field of cross-disciplinary chemical research and the enormous progress that has been made in the field of natural product biosynthesis over the past 20 years.” “It is now clear that synthetic chemistry, along with molecular biology and biochemistry, can be used to decipher the intricate details of assembly and tailoring of complex natural product molecules,” he adds. “In turn, these fascinating biosynthetic systems are providing access to novel biochemical processes that can inspire chemists in new ways as they probe new reaction mechanisms and develop strategies for constructing and functionalizing complex organic molecules.”—SUSAN AINSWORTH It might be said that Erik J. Sorensen relishes taking on meandering pathways. His career as an organic chemist is centered on finding quick routes to complex molecules, a philosophy that nicely meshes with his passion for distance running. After an injury dashed Sorensen’s childhood dream of becoming a professional athlete, he discovered chemistry during his undergraduate years in Roger Hahn’s lab at Syracuse University, where he received a B.A. in 1989. Sorensen then moved to the University of California, San Diego, where he pursued a Ph.D. with K. C. Nicolaou. There, he contributed to a total synthesis of Taxol and coauthored the book “Classics in Total Synthesis: Targets, Strategies, Methods” with Nicolaou. After earning his Ph.D. in 1995, he became a National Science Foundation Postdoctoral Fellow in Samuel Danishefsky’s group at Memorial SloanKettering Cancer Center, in New York City. He began his independent career at Scripps Research Institute in 1997 and moved his
ACS NATIONAL AWARDS
COURTESY OF ERIK SORENSEN
This installment concludes C&EN’s coverage of ACS national awards for 2009. A profile of M. Frederick Hawthorne, the Priestley Medalist, along with his Priestley Address will be in the March 23 issue. The awards banquet in Salt Lake City, at which all awards except for the Arthur C. Cope Award and Scholars will be presented, will be held in the Grand America Hotel Imperial Ballroom on Tuesday, March 24. It starts with a reception at 7:30 PM followed by dinner and the Priestley Address at 8:30 PM. Tickets are still available; they cost $130 each and may be purchased online at www.acs.org/saltlakecity. The 2009 Arthur C. Cope Scholar awardees will be honored at the 238th ACS national meeting in Washington, D.C., on Aug. 16–20. Nominations are closed for the 2010 awards cycle; recipients will be announced shortly. ACS is soliciting nominations for 2011 national awards, which are due on Nov. 1, 2009. Forms for nominations and supporting information as well as a detailed description of ACS national awards are available online at www.acs.org/awards. Nominations of women and people from populations currently underrepresented in the sciences are encouraged.
research group in 2003 to Princeton University, where he is the Arthur Allan Patchett Professor in Organic Chemistry. Sorensen, 42, “is a pioneer in his field while being a true historian in the art of natural product synthesis. He is a scholar at the highest level,” says his Princeton colleague David W. C. MacMillan, the A. Barton Hepburn Professor of Organic Chemistry. Sorensen’s research merges that historical appreciation with modern chemical strategies and creative flair, MacMillan adds. For example, Sorensen’s group harnessed the strain-releasing fragmentation of a small ring, one of the earliest free-radical rearrangements reported in organic chemistry, with key examples dating back to the 1950s, to achieve the total syntheses of guanacastepenes A and E, natural products with potential antibiotic activity. Furthermore, several of Sorensen’s achievements rely on a reaction recognized since the 1920s, again early in the annals of chemistry—the Diels-Alder reaction. In particular, his colleagues cite his enantioselective synthesis of the natural product FR182877 (cyclostreptin) as a standout example of taking classical reactivity to new heights. Guided by a proposed biosynthesis, Sorensen’s group showed that cyclostreptin’s complex multiring structure could spontaneously emerge from a large single-ring precursor through a double Diels-Alder reaction. The work enabled basic research into cyclostreptin’s microtubule-stabilizing properties at the National Cancer Institute. The achievement is “a brilliant and representative example of Sorensen’s genius in Sorensen the art of total synthesis,” says WWW.CEN-ONLINE.ORG
Nicolaou, now the Darlene Shiley Professor and chair of the department of chemistry at Scripps. “We look to nature for insights that might allow us to rapidly build complexity, but we’re not dogmatically connected to bioinspired pathways,” Sorensen comments. Indeed, a challenging synthesis puzzle motivated his group to build a new nitrogen-containing diene for use in the Diels-Alder reaction. “All of Sorensen’s achievements demonstrate the same spirit at work, one that makes the attempt to transcend purely chemical aspects of his science,” says Albert Eschenmoser, professor emeritus at Swiss Federal Institute of Technology. In addition to his work in the total synthesis arena, Sorensen has delved into proteomics. In those efforts, he collaborated with Benjamin F. Cravatt of Scripps to build reactive molecular probes for exploring complex protein samples. Sorensen has received many awards, including the 2001 AstraZeneca Award for Excellence in Chemistry, the 2001 Eli Lilly & Co. Grantee Award, the 2002 Pfizer Global Research Award for Excellence in Organic Chemistry, the 2004 Bristol-Myers Squibb Unrestricted Grant in Synthetic Organic Chemistry, and the 2005 Roche Award for Excellence in Organic Chemistry. When he’s not out for a jog or dreaming up creative chemistry, Sorensen tends to another hobby—playing the drums. “Loud and fast,” he specifies. Though he enjoys many styles of music, he’s partial to the work of Neil Peart, the drummer and lyricist for the rock band Rush.—CARMEN DRAHL
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