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In brief
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This year’s Priestley Medalist, K. Barry Sharpless, is a master at getting molecules to do his bidding. He’s pioneered two influential areas of chemistry: asymmetric catalysis and click chemistry. And he’s inspired legions of chemists. Read on to find out how this molecule maker went from fishing in Manasquan, New Jersey, to winning the Nobel Prize in Chemistry.
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The Molecule Whisperer 2019 Priestley Medalist K. Barry Sharpless works magic in the world of molecules BETHANY HALFORD, C&EN BOSTON
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he best way to get an idea of what it’s like to interview K. Barry Sharpless is to play pinball. Once his mind winds up, you never know exactly where the conversation will bounce to. Topics of discussion can jump from fishing on the Jersey shore to acetylcholinesterase inhibitors to his beloved pet mutt, Batty, in a matter of just minutes. And Sharpless will be the first to admit that his train of thought isn’t necessarily linear. “I usually don’t answer questions,” he admits. “I don’t speak in full sentences, and I have a hell of a time writing.”
Research in California, a list of awards— Sharpless’s friends, former students, and colleagues all reach for words like “ec- including half the 2001 Nobel Prize in centric” and “unconventional” when asked Chemistry—that fills two single-spaced pages on his curriculum vitae. This year to describe him. But the description they he’s being recognized with the 2019 all eventually arrive at is that he “thinks like a molecule.” The phrase seems to have Priestley Medal, the American Chemical Society’s highest honor, for “the invention originated with Sharpless himself—he of catalytic, asymmetric oxidation methadvised students during his time teaching ods, the concept of click chemistry and undergraduate organic chemistry to do development of the copjust that. Those who know per-catalyzed version of the Sharpless say it sums up PRIESTLEY azide-acetylene cycloaddihis uncanny ability to MEDAL PROFILE tion reaction.” know how molecules will “Receiving the Priestley behave and how he can get K. BARRY SHARPLESS came as a real bolt from them to do his bidding. the blue and is something During a career that I never expected,” Sharpspans almost 50 years, less says. Unlike many past this chemical intuition Priestley Medalists, he’s has earned Sharpless, who shied away from science is W. M. Keck Professor politics and from serving of Chemistry at Scripps APRIL 1, 2019 | CEN.ACS.ORG | C&EN
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as a chemistry journal editor. “I am just a chemist who’s spent my life trying to make it possible for chemists to do better chemistry,” he says.
Sharpless didn’t foresee a career in the central science. Although he was a pre-med major until his last semester in college, he was driven by his love of the sea and harbored thoughts of becoming the captain of a fishing boat—just like his uncle Dink, who Sharpless describes as the black sheep of the family. Sharpless grew up in Philadelphia but spent the summers of his youth exploring the Manasquan River where it meets the New Jersey shore. His family had a cottage nearby, and he says his mother would let him roam free. “That’s where I learned about life, about everything that I’m curious about,” he says. As Sharpless grew older, he began to sail with his uncle Dink, catching fish on the Manasquan. Sharpless attended a Quaker school in Philadelphia that he credits with teaching him to read and speak German (a skill he’d find useful later for combing the old chemical literature). But he says he spent most of his time daydreaming about fishing. “I didn’t learn much in school except what I needed to do to get As,” he remembers. Sharpless began his undergraduate studies at Dartmouth College in the fall of 1959. As a freshman, he broke his leg in a skiing accident and spent the whole winter term hobbling to the library on crutches to study organic chemistry. “Not only did I like it, but I could remember everything,” he says. “I don’t think there was a question they could ask me that I couldn’t answer.” “He was the top student among the 135 Dartmouth undergraduates in the first course I taught directly out of graduate school in the fall of 1960,” says Tom Spen-
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◂ Sharpless, age 24, with some prized catches in Monterey Bay, California
▾Jan and Barry Sharpless’s children, from left: Will, Hannah, and Ike, circa 2000
cer, Dartmouth chemistry professor emeritus. “As a novice, I had no basis of comparison to appreciate how talented this obviously very bright and manically energetic young man was, but fortunately I did not discourage him from pursuing a career in science.” Those were the days when chemical stockrooms were essentially open to students, Spencer says, and Sharpless couldn’t resist the chemicals’ siren call. “People like me, if we get into a lab, then we’ve got a chance to really fall in love,” Sharpless says. “I memorized all the chemicals in the stockroom—the smell, the taste,” he says in a tone that makes it tough to tell if he’s joking. Whether he’s serious or not, this type of sensory experience isn’t recommended, safety-wise. But Sharpless never stayed at Dartmouth during the summer to do research. “I loved fishing more,” he says. Sharpless’s father, a surgeon, “had assumed that Barry would go to medical school and would follow in his footsteps,” Spencer says. But seeing Sharpless’s talent in chemistry, Spencer encouraged him to pursue a graduate degree in the field. “One day his father called me and said, ‘What are you doing to this boy?’ ” Spencer remembers. “His father wondered who the hell I was and why I was trying to mess with Barry’s life. But when I described Barry’s talents, his father
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Jan and Barry Sharpless in Switzerland in 1987
backed off and later became an enthusiastic supporter.” For graduate school, Sharpless moved west to Stanford University, where he worked on cholesterol biosynthesis with Eugene E. van Tamelen as a graduate student and organometallic chemistry with James P. Collman as a postdoctoral fellow. But the most influential event to occur during Sharpless’s time at Stanford was when he met Jan Dueser at a beach party. “Jan was the date of Doug Walgren, one of my friends from Dartmouth,” Sharpless recalls. The two eloped a year and a half later, in 1965, and Sharpless credits her with anchoring him and for a good deal of his success. For example, much of the eloquent writing that appears under K. Barry Sharpless’s byline, such as his Nobel autobiography and a story describing how he lost his vision in one eye during an explosion because he wasn’t wearing safety goggles, was, in fact, written by Jan. (A funny aside: Walgren spent seven terms in the US House of Representatives, elected from Pennsylvania’s 18th District. He and Sharpless remained friends, and when Sharpless won the Nobel Prize in 2001, Walgren called and Jan answered. He said to her, “Just think, Jan, if I had married you, maybe I could have been president.”)
A dramatic first act with asymmetric oxidations In 1969, Sharpless moved to Massachusetts to study enzymology as a postdoc in
The resulting performance piece was Konrad E. Bloch’s lab at Harvard University. held in a steeply raked auditorium at MIT. The following year, he became an assistant On a big, square plinth in the center of the professor at the Massachusetts Institute auditorium, Sharpless and Kovachevich of Technology, where he spent seven years rippled large sheets of tissue-like paper to before taking a faculty position at Stanford. which (+)-disparlure had been applied. Three years later, though, he rejoined the “The idea was that he would release all Chemistry Department at MIT. these gypsy moths at the top of the room At Stanford, Sharpless had been trying and he was going to show how they make to develop ways to asymmetrically oxidize a beeline for these papers coated with the double bonds, transforming the flat C=C pheromone,” says Rick Danheiser, a chemlandscape into only one of two possible istry professor at MIT. oxygen-containing 3-D shapes. He rememThe moth pupae were ordered from an bers feeling that his work had stagnated. army research lab so that they would hatch “It was a month after I told them I was on the day of the performance, Jan recalls. leaving to go back to MIT that we got the “They hatched right on schedule, but sadly, breakthrough on asymmetric epoxidation,” he says. Had his group made the discovery a their little wings weren’t fully developed, month earlier, he says, “I probably wouldn’t so the guys couldn’t fly,” she says. “Not to worry. Sex being what it is, the fellas were have left.” released at the top of each aisle and they After years of development in Sharpscrabbled and tumbled their way down the less’s lab, the reaction he and his postdoc steps, then tried hop-flying from the floor Tsutomu Katsuki eventually discovered up to the platform.” was the Sharpless asymmetric epoxidation, Sharpless had performed a similar which uses titanium compounds and chiral demonstration for his undergraduate ligands to transform primary and secondorganic chemistry class a year earlier, ary allylic alcohols into 2,3-epoxyalcohols recalls Danheiser. On that occasion, the in an enantioselective manner. The reacmale moths’ wings had tion showed that it was fully formed, but the possible to use metals in (+)-disparlure had been a predictable way to oxO blown throughout the idize double bonds with room by the ventilation high enantioselectivity system. Once released, and was part of the work (+)-Disparlure the gypsy moths were cited by the Nobel comfrantically flying everymittee. To demonstrate where, Danheiser rememthe reaction’s utility, bers. They were landing Sharpless’s group used it on the students, and panic to make (+)-disparlure, ensued. the chemical that female Although the gypsy gypsy moths use as a sex moth display didn’t go as attractant. planned, Danheiser says The pheromone apparit was demonstrative of ently has some staying Sharpless’s teaching style. power. A major gypsy “Barry was always trying moth invasion occurred to find some sort of way in New England in 1980, of entertaining the class while the Sharpless lab but also doing it in an was relocating from StanSharpless showed the informed way,” Danheisford to MIT. When some usefulness of asymmetric er says. “His passion for of the Sharpless group epoxidation by harnessing it members got off the plane to synthesize the gypsy moth chemistry was apparent in his lectures, and it was in Boston, moths attacked pheromone (+)-disparlure. infectious.” their “laundered but still The asymmetric epoxidation elicited alluring clothing” that they had worn in the incredible excitement from the chemistry lab during (+)-disparlure’s synthesis, Jan community, says Harvard’s Eric Jacobsen, Sharpless recalls. who was a postdoc in Sharpless’s lab from News of the gypsy moth attack reached 1986 to 1988. “It wasn’t the first reaction Kathy Halbreich, who was director of the that used metals in a useful way for organic Albert and Vera List Visual Arts Center synthesis, but it was really the first reaction at MIT at the time. In 1985, performance that allowed chemists to control stereoartist Thomas Kovachevich was going to chemistry in a predictable way,” he says. be in residence at MIT, and Halbreich While Jacobsen was at MIT, he worked asked Sharpless if a collaboration might be with Sharpless on the reaction that is possible. APRIL 1, 2019 | CEN.ACS.ORG | C&EN
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The second act clicks into place
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A penguin observes Sharpless resting on an Antarctic beach in 2003.
Prize,” Jacobsen says. So Sharpless would be invited to give lectures. “Instead of talking about his work in asymmetric oxidation, he started talking about this idea that seemed to come completely out of left field,” Jacobsen continues. “He decided that what we need is good reactions. Something that will connect things in a completely reliable way. That’s really not how chemists usually think. Chemists think, ‘Well, here’s a molecule that I want to make; let me think about the best way to make it,’ or ‘Here’s some reactivity that I want to understand and exploit; let me see what I can do with it.’ ” But Sharpless was saying that chemists needed a reliable reaction that would connect things under all different types of circumstances. “And I remember audiences just looking at each other thinking that he had lost his mind,” Jacobsen says. “I’d like to say that at the time I knew that he was onto something, that I knew him well enough and had experienced his genius enough to know that he was onto a really good idea. But the truth is, I don’t think that anybody saw what was coming. Only Sharpless saw that this idea he had to discover great reactions—just any reaction that could connect things and be totally general—would be transformative in chemistry. “He talked about it before he had the reaction,” Jacobsen adds. “And I remember people being almost angry with him when he gave talks because he was invited
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materials science, and surface science. Although there are several different click reactions, the premier example is the copper-catalyzed azide-alkyne cycloaddition (CuAAC). This reaction weds an azide and an alkyne to form a 1,2,3-triazole, which links the two moieties together. Reactions between azides and alkynes weren’t new. Reports of them date back to the early 20th century, and Ludwig Maximilian University Munich’s Rolf Huisgen is typically credited with solidifying the concept in the late 1950s. But the transformation that Huisgen devised took a long time, required elevated temperatures, and produced two different regioisomers—hardly the spring-loaded reaction Sharpless was hunting for. In 2002, Sharpless and his group reported that if they used copper(I) to catalyze the reaction, they could get it to go instantaneously, in water, at room temperature, and it produced only one regioisomer. Sharpless says synthetic chemists had a distaste for click chemistry when he first started talking about it. “It was too simple,” he says, and that made it an affront to them. But scientists of other stripes saw how useful the transformation could be. They could use it to guarantee linkages in all sorts of systems. Surface scientists could use click chemistry to anchor a molecule to a surface; biochemists could use it to latch a biomolecule onto a reporter molecule. These folks just need bond-making chemistry that works reliably and under almost any conditions, Sharpless says. “Those who need bonds, In 1990 Sharpless moved to Scripps, lured by Richard Lerner, who was president like materials scientists and biologists who have to grab hold of who knows what from of the institute at the time. “It was obvious that he was a chemical genius,” Lerner says. the sewer, basically, they don’t ask questions. They’re so thankful to have someDuring his time at Scripps, Sharpless thing that works.” began shifting from asymmetric catalysis “Click chemistry was entirely Barry’s to what would become click chemistry. The central idea behind click chemistry is to use idea, entirely his inspiration,” says the Georgia Institute of Technology’s M. G. molecular building blocks that are spring Finn, who earned his PhD in SharR1 pless’s lab in the 1980s and, as a colleague at Scripps, worked with N N N Cu(I) catalyst Sharpless on click chemistry. “I R1 N+ - + R 2 N N can take some pride in helping him R1, R2 = various R2 articulate the vision and developing the details of the concepts, but I The copper-catalyzed azide-alkyne cycloaddition was really following Barry’s lead every step of the way.” is click chemistry’s premier reaction. Click chemistry has been an undeniably useful tool, but most people loaded to covalently “click” together only didn’t see it that way at first, Harvard’s with one another. Jacobsen says. He recalls when Sharpless Sharpless and Jan came up with the began lecturing about the idea. “By that click chemistry moniker together. He says time he had made two great discoveries in he didn’t think it would catch on, but the asymmetric catalysis, and he was really the alliterative label has stuck, and click chemistry has come to find use in vastly different giant in the field. Everybody was pretty sure at that point that he’d get a Nobel realms of science, including biochemistry, now known as the Sharpless asymmetric dihydroxylation. In this transformation, an alkene reacts with osmium tetroxide in the presence of a chiral quinine ligand to form a single diastereomer of a vicinal diol, in which there are two –OH groups on adjacent carbons. It’s another one of the chirally catalyzed oxidation reactions that garnered Sharpless the Nobel Prize. “Barry gets incredibly excited about things when a result catches his attention, but it isn’t always clear to people in the lab what that will be,” Jacobsen says. “I was very fortunate because I was able to work on something that did get his attention. And once you got his attention, it was incredible. It was amazing the way he could just dive into a problem and become absorbed by it.” Jacobsen recalls one Thanksgiving Day during his postdoc when he was visiting his mother in New York City. “The phone rings, my mother picks up, and it’s Barry Sharpless,” he recalls. “She knew enough about working in lab to know that if your adviser is calling you on Thanksgiving Day, it must be a bad thing—there’s a fire in my hood or something.” Jacobsen nervously took the phone and found that Sharpless simply wanted to talk about chemistry. “He just wanted to follow up on a conversation we’d had a couple days earlier because he just couldn’t stop thinking about it.”
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to talk about asymmetric catalysis and he started talking about this crazy idea, describing a reaction that he hadn’t even discovered.” “Definitely a lot of people thought he was out of his mind,” Finn agrees. “Here he had one of the premier labs for asymmetric catalysis, and from the outside it looked like he wanted to do something completely different. Then he proceeded to say that what he wanted to do differently was to try to teach organic chemists a completely different way to do their science,” he says. “Many didn’t understand what he was getting at, or thought they understood it and dismissed it.” But, Finn adds, time has shown that his concept has had an undeniable impact in the molecular sciences. “I don’t know why anyone would think Barry was crazy, unless they were paying no attention to what was going on in the fields of bioorthogonal chemistry and chemical biology,” says Stanford’s Carolyn Bertozzi, an early adopter of click chemistry. “Maybe history will look back on Barry’s copper-mediated reaction, which is surely one of the most important reactions in chemical biology and drug discovery, as
a point where chemists in the mainstream of synthetic reaction development finally learned how important they could be for biologists.” “Barry wants to develop chemistry that will change the world or do something that you couldn’t otherwise do,” says MIT’s JoAnne Stubbe, who was Sharpless’s
colleague for a few years and remains his friend. Click chemistry is a testament to his creativity, she says. “Everybody and his brother uses it.”
early years as a professor at the institute. Buchwald noticed that Sharpless had the prized book series Comprehensive Organometallic Chemistry, which in 1985 cost several thousand dollars—money Sharpless had paid from his personal funds. Buchwald says he told Sharpless he People who know Sharpless say that you was impressed he owned the expensive series. “The next day when I got into my can’t get a true sense of who the man is by office he had taken the whole series and reading his papers and learning about his put it on my desk and given it to me,” science. “You really have to interact with Buchwald says. “Later, it turns out, he him and experience his wisdom one on needed it back. But instead of asking me to one,” Scripps Research’s Phil Baran says. give it back, he bought another set.” “He is incredibly kind and warm but also One of Sharpless’s current graduate very shy at times. He prefers chemicals to students, Gencheng Li, tells how when people. Discussions with him can go for he arrived at Scripps, he didn’t know how hours if you keep it to chemistry.” to swim. When Sharpless learned of this, “His encyclopedic knowledge of evhe signed Li up for sessions with a swim erything synthetic can be challenging to coach, telling him that he couldn’t live in keep up with and a little intimidating,” San Diego and not know how to swim. says Gary Siuzdak, another colleague While Sharpless has a reputation for at Scripps. “So many of my memories being hands off as a mentor, his students of him start with a visit to his office to say they learned by following his example. quickly drop something off, or to ask “Risk taking was always safe in Barry’s his thoughts, and 3 minutes turned into lab,” says Antonella Converso, director 3 hours of a controlled tornado of ideas in Merck & Co.’s Discovery Chemistry and excitement.” Department in West Point, Pennsylvania, That’s not to say Sharpless is without who did her PhD with Sharpless at Scripps his flaws. He would be the first to admit from 1998 to 2003. “You always could go in and say, ‘I tried this and it didn’t work,’ and there would be no repercussions for trying ambitious reactions. That taught me that the good science is not on the beaten path. The good science is in the ideas that are sideways. You just have to keep going with your eyes open and not be afraid to fail.” “People say that he has incredible intuition, but I don’t think that does him justice,” Harvard’s Jacobsen says. “I think it’s much more than intuition. He knows how to think in ways that other people simply can’t.” “Somebody as successful One of Sharpless’s as Barry, and someone who prized German seems to do it so effortlesschemistry texts, ly, provokes a lot of envy in covered in Sharplesshis competitors,” says Julius style notes Rebek, Sharpless’s longtime friend and colleague at Scripps. “I think Barry has shown time and time that he’s not a great public speaker. And again that he comes up with these useful, the way his brain is wired makes it tough groundbreaking milestones. His inventive for him to focus on one thing. Despite his methodologies have endured and enriched shortcomings, his friends and colleagues generations of chemists.” The Priestley all say that he’s got a good heart and is Medal, Rebek says, is “an apt recognition generous to a fault. of his huge body of work and its service to MIT’s Stephen L. Buchwald recalls going to Sharpless’s office during Buchwald’s the chemical community.” ◾
A down-to-earth genius
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