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SYNTHESIS
Organic chemists champion their future TIEN M. NGUYEN, C&EN WASHINGTON
P
aul Wender was standing center stage, delivering one of the final presentations of the 45th National Organic Chemistry Symposium (NOS). His talk had gone 20 minutes over the allotted time, but the crowd showed no signs of stirring. Wender, a renowned chemist and Stanford University professor, was holding the audience in thrall as he neared the end of his description of an unpublished synthesis of bryostatin 1, a compound that has shown promise for treating cancer and Alzheimer’s disease and possibly helping eradicate HIV. Isolating bryostatin 1 from natural sources is incredibly laborious, Wender pointed out. “That’s why you need folks like us” to make it. His lab had devised a 29-step route to the natural product, down from a previously reported 57-step synthesis. The final step in Wender’s new route ends with a deprotection reaction. “And it didn’t work,” he said, drawing sympathetic groans from the audience. After a beat of silence, beaming, he added: “I’m just kidding—it did.”
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and a rousing lineup of speakers. The 14 speakers shared the latest advances from their labs while also addressing the future of organic chemistry. Not only did they give advice to student attendees as future torchbearers for the field, but some of them also called for the community to embrace collaboration to aid scientific progress. Still others mounted a defense of the field, wrestling directly with the question, is organic chemistry dead?
Miles of open space
The crowd’s reaction to Wender’s talk reflected the high level of enthusiasm for On the morning of June 26, attendees and personal investment in the chemidrew close to the stage in the Mondavi cal achievements discussed during the Theater, filling the seats in the front third June meeting. NOS, a biennial gathering, of the expansive auditorium. They wantattracted about 500 organic chemists ed to get good seats in anticipation of from 42 companies and more than 150 the first plenary session of the meeting, universities and colleges this year. Held featuring talks by Phil Baran of Scripps over five relentlessly Research Institute sunny days at the California and Sarah University of CaliforReisman of Calinia, Davis, the symfornia Institute of posium squeezed in Technology. opportunities to enUp first, Baran flew joy Northern Califorthrough a discussion nia in the afternoons of one of his lab’s between nightly postresearch programs, er sessions averaging which uses redox ac70-plus presenters —Paul Wender, Stanford University tive esters and metal
“There are more problems than people to solve them.”
C R E D I T: S EA N A RO N OW
Speakers at the 2017 National Organic Chemistry Symposium defended the field and called for more collaboration
Attendees arrive at the 45th National Organic Chemistry Symposium, held at UC Davis.
NIGMS, he said that synthesis isn’t facing And there are innumerable compounds catalysts to swap the ubiquitous carboxylic any more stress than other scientific disthat are still being discovered and that acids on molecules for a number of useciplines and that he hopes that chemistry have never been made. Marisa Kozlowski, ful functional groups, including alkenes, students aren’t going to other areas out of a chemistry professor at the University of alkynes, and boronate esters. One subfear of a lack of funding opportunities. Pennsylvania, illustrated this point during strate table after another glided across the Kozlowski responded by reiterating her the audience participation portion of her screen as he demonstrated the scope of sentiments about the need for organic retalk. each reaction. search and stressed to the student attendDuring her presentation, Kozlowski In a series of side-by-side comparisons, ees, “I think there’s miles of open space.” showed that her group had used a miBaran showcased the utility of the decarAlthough Baran wasn’t present for the croscale, high-throughput screening boxylative alkenylation reaction to enable exchange, he told C&EN that he disagrees strategy for reaction discovery. With this streamlined total syntheses. In one examwith Lees and emphasized that there artechnique, the team tested dozens of ple, he showed how his group constructed en’t nearly as many institutions funding metal catalysts for their ability to oxidathe natural product cladospolide B in five pure synthesis as there are institutions tively couple phenolic compounds. The steps, whereas a previous route took 14 funding fields like biology. researchers quickly sidestepped unproand, Baran said, “unfortunately” used the C&EN reported data released by the ductive catalysts, such as iron-based comWittig reaction. National Science Foundation earlier this According to Baran, academics “bend to pounds, which they may have otherwise year that showed chemistry received spent time optimizing, before identifying the whims” of the Wittig, which relies on 2.8% of the total funding for science in several successful catalysts, such as a phosphorus ylide compounds to convert 2015. Chemical and materials engineering chromium-salen compound. carbonyl groups to alkenes and may reeach received 1.4%, and quire various adjustments physical sciences such as of oxidation state and In response to discussions at NOS of whether organic chemistry is dead, astronomy and physics chemoselectivity considMary K. Boyd, a provost at Berry College, tweeted the following: took in a total of 4.6%. erations. He added that Meanwhile, life sciences the Wittig will always be such as biology received needed in some situations 60.8%. and that at the introducTehshik Yoon, a protory level it’s important fessor at the University to know the foundational of Wisconsin, Madison, reactions; otherwise you’d also ruminated after his be doomed to reinvent talk on the question of the wheel. whether organic chemBut at the same time, istry’s fate was sealed. “it’s important for us to “How would you know” if stay vigilant that organthere was nothing left to ic synthesis be useful,” discover? he asked. he said. One idea that Reflecting later on his remarks, Yoon Showing a slide full of oxidatively couappears regularly in various corners of said pronouncements that some scientifpled biarene products, she asked, by a science—and that Baran disputes—is that ic field is dead crop up every few years. show of hands: “What percentage of these organic chemistry is a mature field and As chemists, “we spend a lot of our time molecules do you think have been previtherefore has nowhere left to go. thinking about what we don’t yet know. So ously reported?” The question was multiFor instance, in a Nature editorial from for me, the idea that anyone could know ple choice. The answer that garnered the 2011, prominent scientists George Whenough about the entire field of chemistry most hands in the air was 25%. itesides at Harvard University and John to be able to predict what the next big It turned out the crowd was right: Only Deutch at Massachusetts Institute of thing is, or what things don’t need to be Technology described academic chemistry, a quarter of the compounds had been studied any further, that entire idea is realmade before, a fact Kozlowski said she including organic chemistry, as a mature ly alien to me,” he said. found surprising given the simplicity of science and advocated an overhaul of the Since we don’t know what we haven’t the molecules. She closed by noting that field to shift focus to addressing global yet discovered, chemists should be enmuch remained to be done in oxidative problems. gaged in all kinds of research, Yoon arcoupling, bolstering the argument that orReisman, who presented her group’s gued, adding that the best science happens ganic chemistry is far from dead. total syntheses of the natural product when it’s something that you’re passionate Prompted by these remarks, Robert ryanodol and revealed a nearly complete about. Lees, a program manager at the National construction of the compound talatis“Love the stuff you love,” he said. Institute of General Medical Sciences amine, followed up on the thread about who oversees synthetic organic chemistry the field’s maturity. Some chemists argue grants, commented that several of the that with unlimited resources it’s now speakers so far felt the need to defend possible to construct any molecule, but the field of organic chemistry and asked, even if that were true, she said, it’s not “Where is this feeling that you’re under enough. She points out that realistically, Well aware that NOS tends to attract attack coming from?” compounds must still be made with limstudents, many of the speakers took the Lees wondered if the feeling of threat ited resources and in useful quantities, opportunity to address the “new people,” stems from worries about funding for which requires the talents of synthetic as Stanford’s Wender called them. organic research. From his perspective at chemists. “There are more problems than people
Collaboration, not competition
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most of the already discovered natural to solve them,” he said, citing statistics products, which as of 2012 number apon the more than 7,000 orphan diseases proximately 240,000, according to the waiting for treatments and the 6,500 new “Dictionary of Natural Products.” More infections of HIV daily. This will change than 75% of linear natural products could only through collaboration, not competibe synthesized with only 1,450 fragments, tion, he added. Wender took his own advice, setting up a new collaboration at the meeting with David Olson, a former Stanford student and now assistant professor at UC Davis. Their collaboration focuses on using bryostatin and other analogs to induce biological changes that could influence cognitive abilities affected by Alzheimer’s disease and other neurological disorders. Martin Burke, a Professor Tehshik Yoon presented at this year’s NOS meeting. chemist at the UniBurke contends. versity of Illinois, Urbana-Champaign, One of the many questions Burke remade another plug for collaboration at ceived after the talk was how he would NOS. During the final talk of the conferconvince organic chemists to come toence, he pitched a “moon mission” for gether and rally around this project, given the chemistry community to consider. that chemists tend to stick to the areas The so-called Natural Producteome they’ve already carved out for themselves. Project, proposed as a massive effort to He responded that the umbrella for such synthesize any natural product, could be a project is huge and has great collateral to chemists what the Human Genome benefit for the community, including Project was for biologists or what the drawing more funding to the field. search for the Higgs boson has been for Within this project, he said, chemists physicists, Burke said. would “still get to do what they love.” In a 2015 Science article, he proposed a road map to automate small-molecule synthesis using iterative reactions that hinge on an N-methyliminodiacetic acid boronate ligand to stitch together molec“The beauty of NOS is the combination ular building blocks (DOI: 10.1126/science. of plenary and poster sessions,” said Mary aaa5414). K. Boyd, a provost at Berry College and The paper evoked a strong and mixed chair of the executive committee of the reaction from the chemical community. ACS Division of Organic Chemistry. Some chemists supported the idea as a Through the meeting’s talks, students boon for making drug candidates in the learn from not only the cutting-edge sciearly stages of discovery, while others ence but also the scientists presenting pointed to the failure of previous technolthe work. For instance, Moriah Locklear, ogies, such as combinatorial chemistry, to a graduate student at the University of transform drug discovery. Other chemists Nebraska, Lincoln, said that in addition doubt the method’s ability to access more to the science presented in Reisman’s complex structures. plenary talk, she appreciated Reisman’s Still, Burke remains passionate about honesty in discussing reactions that didn’t one day “handing the power of synthesis work. As a student in the trenches of reacover to our nonchemistry colleagues.” tion development, Locklear said she finds Now his lab is collaborating with Jeffrey these examples comforting. Skolnick’s group at Georgia Institute of “I enjoyed seeing how someone like Technology to compute how many buildSarah Reisman thinks,” Locklear added. ing blocks it would take to synthesize This year’s NOS had an “amazing” line-
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C R E D I T: S EA N A RO N OW
Spotlight on students
C R E D I T: TI E N N GU YE N /C & E N
questions before the postdoctoral reup of speakers, said Kay Brummond of the searchers or faculty, who were standing University of Pittsburgh, who organized against the back wall. the conference along with the University Frndak asked the first question: “Can of Arkansas’s Matt McIntosh and local cowe go over the Wittig?” Others chuckled. chairs Dean Tantillo and Annaliese Franz. “Sure, since Baran’s not here,” someone The moderate size of the conference replied, referring to Baran calling attenalso gives students the opportunity to engage with speakers and receive feedback tion to academics’ attachment to the reaction earlier in the conference. on their work during the poster sessions. Prompted by Brisbois and Katz, stuKatt Frndak, a rising senior undergradudents gave descriptions of each mechanisate at Calvin College, gave a spirited overtic step and correctly identified the reacview of her research in alkaloid synthesis tion’s key intermediate, the Wittig ylide, at the opening poster session, excitedly which contains neighboring atoms that gesturing and memorably describing possess positive and negative charges. the loss of a “beloved functional group” Other requests included a review of during her research. pericyclic reactions, the Suzuki reaction, Frndak especially appreciates the opand “everything that Barry Carpenter portunity to interact with colleagues at presented.” Carpenter, an honorary proNOS. She recalls last summer being asked by an older, female donor who was passing fessor at Cardiff University, had given a through the lab on a tour of Calvin College mind-bending talk that included advanced mathematical theory on the flawed way in if she enjoyed doing chemistry. “Have fun which chemists think of transition states. because I couldn’t,” the donor said, alludFrom the back of the student session, ing to a not-so-distant past in which womChristian Hamann, an associate chemistry en were not encouraged to enter science, professor at Albright College, estimated an exchange that has stayed with Frndak. that perhaps 10 people in the audience Another student-focused feature of grasped the talk in its entirety, and admitNOS is the Undergraduate Context Sested to understanding just a fraction of the sion offered midway through the contalk even though it was his second time ference. The pizza-catered session gives seeing it. students a chance to ask questions about “My point is that we come to these any of the chemistry presented during the meetings to learn and sometalks that they had trouble times we’re overwhelmed by following. Calvin College the vocabulary and the conLed by Ronald Brisbois, a undergrad Katt chemistry professor at MacaFrndak presented her cepts because it’s not what we do every day,” Hamann said. lester College, and Jeff Katz, poster at NOS. “So if you’re feeling overwhelmed by the vocabulary and everything else, welcome to the club.” Afterward, a group of students said they enjoyed the session, especially knowing that they weren’t alone in feeling in over their heads, and wished only that it had lasted longer. Overall, the meeting was “exceptional,” Wender said, adding that he a professor of chemistry at Colby College, attends a lot of conferences. It brings this free-flowing hour has been a fixture together young people “that will form of the conference since 2005. The session bonds—pardon the expression—that will grew out of a suggestion by K. C. Russell, last a lifetime,” he said. Seeing the stua professor at Northern Kentucky Univerdents’ enthusiasm reassured him about sity, who sat in the front of the crowded chemistry in the years to come: “These are room. possibly going to be the collaborators of Brisbois and Katz explained that stuthe future.” ◾ dents were asked to answer each other’s
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