SCIENCE & TECHNOLOGY
ORGANIC SMORGASBORD
ars are involved in signaling and recognition events there and throughout the body. With their synthetic chemistry expertise, the researchers make carbohydrate-based tools for understanding neurobiological conversations. Among other carbohydrates, the group is exploring sulfated Biennial meeting celebrates the breadth of polysaccharides in the chondroitin sulfate CUTTING-EDGE RESEARCH in organic chemistry (CS) class. Hsieh-Wilson’s team is trying to CARMEN DRAHL, C&EN WASHINGTON comprehend how the structures of specific CS carbohydrates relate to their function. The trouble with understanding the role enthusiasm for organic chemistry and its of CS polysaccharides in neurobiology is LANGUAGE INTERPRETATION, building ability to provide tools for tackling tough that they are highly complex, with the sulconstruction, and sports analysis usually problems in a broad range of areas, Sibi fate groups arranged in diverse patterns on don’t come up at chemistry meetings. But noted. The following meeting highlights, the sugar scaffold, Hsieh-Wilson says. Unthey’re apt metaphors for strategies pretaken from the lineup of 13 invited lecturderstanding the message a complex polysented to the more than 700 organic chemers, demonstrate that breadth. saccharide sends to the nervous system is ists at the 41st Biennial National Organic like reading a set of instructions without Chemistry Symposium (NOS), held at the any familiar words or phrases. University of Colorado, Boulder’s ecoThe team started by trying to figure conscious campus on June 7–11. SUGARY TOOLS DISSECT out what some of the “words” in the CS NOS, first established in 1925, is sponNEURONS’ CHATTER language mean. To do that, they made sored by the American Chemical Society’s BEFORE ATTEMPTING to read a sentence defined disaccharides and tetrasacchaDivision of Organic Chemistry. Organizers or a novel in a foreign language, it helps to rides with sulfate groups positioned at Mukund P. Sibi of North Dakota State Unifirst grasp some grammar and vocabulary precise spots along the carbohydrate versity and Tarek Sammakia and Andrew for the language in question. Linda Hsiehbackbone. They learned that a specific J. Phillips of CU Boulder told C&EN that Wilson and her group at California Instithree-dimensional pattern of sulfates in NOS is known for fostering an intimate tute of Technology are doing their part to a sugar they call chondroitin sulfate-E environment. “This is a big conference, acts as a recognition but there is a very element, binding to personal feel to it,” growth factors in the Phillips said. That was brain and stimulating especially true at the neuronal growth. poster sessions, where Somewhat eminent chemists paradoxically, CS mingled with students polysaccharides are and young scientists also implicated in in front of nearly 400 inhibiting neuronal posters. growth after an inIn line with tra– – jury. Although short dition, an evening OSO 3 – O3SO – – OSO3 O3SO O2C sugar chains worked session feted the – O2C O O HO just fine in the team’s winner of the ACS O O O O HO neuronal growth Roger Adams Award O O HO OH AcNH studies, the chains in Organic Chemistry. OH AcNH Ac = acetyl didn’t seem to have This year’s winner, much effect in growth Andrew Streitwieser SWEET SCAFFOLD Cartoon of natural polysaccharide (left) and of synthetic inhibition assays. So of the University of tetrasaccharide polymer (right). the group sought a California, Berkeley, way to access longer said he was “awed and demystify a decidedly tricky tongue—that polysaccharide structures. It’s tough to humbled” to be joining the distinguished of the nervous system. Researchers are make such sequences, but Hsieh-Wilson’s list of Adams awardees. Streitwieser shared eager to understand communication in the team found a way around the problem. how his early love of theoretical chemistry nervous system because it underpins nerve The researchers mimicked the activity of led to experimental and computational growth, recovery from injuries, and more. longer CS polysaccharides by making synresearch on, among other things, the chemIt helps that Hsieh-Wilson’s team is fluthetic polymers that were decorated with istry of the carbon-lithium bond (C&EN, ent in carbohydrate chemistry because sugdefined CS di- or tetrasaccharide motifs March 2, page 52). Although symposium attendance was Read more symposium coverage on C&EN’s blog, “C&ENtral down slightly this year compared with preMORE ONLINE Science,” at www.cenblog.org/category/acs-meetings. vious years, that didn’t dampen attendees’ WWW.CEN-ONLINE.ORG
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along the polymer chain (J. Am. Chem. Soc. 2008, 130, 2959). Making bioactive polysaccharides might be all about including sulfated motifs in a suitable 3-D framework, Hsieh-Wilson says. The polysaccharides are presumably interacting with proteins involved in nervous system communication, so a polymer framework that’s decorated with plenty of motifs that bind to those proteins may help enhance binding affinity, she says. In unpublished work, the group has used those polymeric tools to demonstrate that a specific sulfated carbohydrate structure inhibits nerve growth after injury and to identify a protein receptor for that carbohydrate. Blocking the structure helped mice regenerate neurons after injury, presumably by counteracting the carbohydrate’s inhibitory activity. Someday, carbohydrate-based strategies such as this one might inspire therapeutic approaches to treating nerve damage, HsiehWilson says. Much of the language of CS polysaccharides remains to be understood, and Hsieh-Wilson’s group is currently working on identifying the roles of other sulfation patterns and applying their findings to ever more complex systems.
tered that second step—selective oxidathe pyramid’s bottom level. From those tion in complex settings. Despite a flurry options on the bottom, Chen and Baran of research in converting C–H bonds figured out the most logical place to start into C–O bonds, it isn’t easy to figure out their synthesis. “Instead of making disconwhere to start functionalizing a terpene nections at specific bonds, we take a more skeleton, which can lead to a highly frusholistic approach and disconnect to yield trating research endeavor. sets of compounds with equivalent oxidaChen and Baran tion states,” Baran says. started their work by deChen demonstrated veloping a framework to the utility of that frameOH ease that frustration. The work experimentally by OH result was a modified apsynthesizing a family OH OH proach to retrosynthetic of terpenes called the Eudesmantetraol analysis—a thought proeudesmanes. She first cess for planning an orconstructed the carbon ganic synthesis—that might be better suitskeleton and then built atop that sturdy ed to the terpene challenge. “The beauty of foundation with a series of site-selective retrosynthetic analysis is it gives people a carbon-hydrogen oxidations, notably one framework, a basis to begin,” Baran says. developed in the Baran group. A carbamate Chen and Baran developed somegroup attached to the eudesmane skeleton thing they call a retrosynthetic pyramid. directed several key transformations. The apex of the pyramid houses a highly The eudesmane study lays out a potenoxidized terpene structure. Each step tial strategy for tackling terpene classes to down the pyramid works backward to come, Baran says. For instance, the tactics progressively less oxidized compounds. for building eudesmane might one day Eventually, the lowest oxidized members serve as a primer for constructing the terare reached, and those compounds form pene equivalent of the Taj Mahal: Taxol.
BLUEPRINT FOR TERPENE CONSTRUCTION IMAGINE THAT you’ve been hired to
construct a building. You know what the building is supposed to look like, but you’re not exactly sure what materials to use to build it and what part of the edifice you should start building first. Sometimes, organic synthesis is like that, says Phil S. Baran, a chemist at Scripps Research Institute. Organic chemists are highly skilled molecular craftsmen, but for some targets, synthetic strategy is still very much a black box. Working with postdoctoral research associate Ke Chen, Baran has developed a potential blueprint for building terpenes, a diverse and highly complex family of natural products (Nature, DOI: 10.1038/ nature08043). Over the years, many teams have considered the possibility of making terpenes the way nature does, Baran says. Nature makes terpenes by first forging a carbon skeleton and then oxidizing designated spots on the skeleton with laserlike precision. Synthetic chemists still haven’t mas-
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Time will tell whether this strategy can be generally applicable for making terpenes, Baran emphasizes. His team’s goal along the way is to plan its syntheses in a way that will make it possible to innovate—by inventing selective oxidations and transformations that get the team where it needs to go.
MECHANISTIC BREAKDOWN FLIP TO A SPORTS CHANNEL on TV, and it’s likely that at some
converts a C–H bond to a C-aryl bond. Pd-catalyzed C–H arylation reactions are a potential complement to metal-catalyzed cross-coupling reactions such as the Suzuki reaction, which are commonly used on an industrial scale. However, Sanford’s reaction currently requires higher amounts of catalyst than would be practical for such applications. Sanford’s graduate student, Nicholas R. Deprez, gained insight into why that was by performing a kinetic analysis. The reaction rate turned out to have a negative third-order dependence on substrate concentration, a rare situation in catalysis. “The more substrate you add, the more slowly the reaction goes,” Sanford
point someone will bust out a Telestrator to analyze a play by doodling onscreen. Telestrator-aided commentary helps viewers understand how O a complicated play helps a team reach a N O goal and can even serve as a critique when Pd N O N Pd O something goes awry. Melanie S. Sanford N 2 +2 also believes that breaking down a comO plex process and analyzing each player’s Pd N moves is a great way to understand what’s O going on and to make something that’s already good even better. Except that Inactive Active Sanford deals with maneuvers on the molecular scale—not on the gridiron. CATALYST CONUNDRUM The active form of this catalyst is in equilibrium with At NOS, Sanford, a chemist at the a catalytically inactive form. Adding more substrate (orange) pushes the equilibrium University of Michigan, Ann Arbor, back toward the inactive species, thereby slowing the reaction rate. proposed a mechanistic play-by-play for a palladium-catalyzed reaction that says. Reducing the amount of catalyst would effectively achieve the same slowdown, she explains. The kinetic data eventually led Deprez to look beyond the key steps involved in the C–H bond transformation. With nuclear magnetic resonance spectroscopy, he examined interactions that happened outside the catalytic cycle between the substrate, an oxidant involved in the reaction, and the catalyst. His data indicate that the substrate gets tied up in nonproductive interactions with the cata iiÌÃÊ1-*É *É *É*É -ÊÀiµÕ Àii Ìà lyst. Two forms of the Pd catalyst are in equilibrium: an inactive complex with one Pd metal center coordinated to two molecules of substrate and an active complex with two metal centers, also conUÊ Õ Ê* ë >ÌiÊ L>ÃVÊ taining two molecules of substrate. UÊ Õ Ê* ë >ÌiÊ L>ÃVÊ É To reach the active complex, “you lose two equivalents of the UÊ Õ«ÀVÊ-Õv>ÌiÊ*i Ì> Þ`À>ÌiÊ1-* substrate, and that’s where this inverse order in substrate comes UÊiÀÀ ÕÃÊ Õ Ê-Õv>Ìi from,” Sanford says. The third equivalent of substrate gets lost via UÊ > }> iÃiÊ-Õv>ÌiÊ Þ`À>ÌiÊ1-*É *É an interaction with the oxidant, she adds. UÊ* Ì>ÃÃÕ Ê* ë >ÌiÊ L>ÃVÊ É *É *É Now that they understand what’s going on, Sanford and Deprez UÊ* Ì>ÃÃÕ Ê* ë >ÌiÊ L>ÃVÊ1-*É have two ideas for improving the reaction: find a way to make the UÊ* Ì>ÃÃÕ Ê-Õv>ÌiÊ *É monometallic form of the catalyst catalytically active or find a way UÊ- `Õ Ê >ÀL >ÌiÊ Þ`À ÕÃÊ É *É*É to keep the catalyst in its bimetallic, active form. They’d like to UÊ- `Õ Ê >ÀL >ÌiÊ Þ`À>ÌiÊ É obtain the X-ray structure of the bimetallic species and determine UÊ- `Õ Ê* ë >ÌiÊ L>ÃVÊ Þ`À>ÌiÊ1-*É *É whether similar intermediates are involved in other reactions. The UÊ- `Õ Ê* ë >ÌiÊ L>ÃVÊ Þ`À ÕÃÊ1-*É *É active form of the catalyst is one of a growing group of bimetallic species that play key roles in transition-metal catalysis (C&EN, UÊ- `Õ Ê* ë >ÌiÊ L>ÃVÊi«Ì> Þ`À>ÌiÊ1-*É June 8, page 10). UÊ- `Õ Ê-Õv>ÌiÊ Þ`À ÕÃÊ1-*É Additional nuances remain to be worked out, Sanford notes. ÜÜÜ°ÃÌV iV>°V What’s most surprising about the reaction mechanism is that it’s very different from that of similar Pd-catalyzed reactions developed in the group, she says. By substituting just one reagent, they change not only the reaction’s dependence on substrate but also the turnover-limiting step of the reaction. With that and other 1 / 1 , , Ê " Ê Ê * 1 , / 9 Ê " , Ê - / qualities of the reactions to be understood, further mechanistic play-by-plays are surely still to come. ■
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