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Biological Chemistry

Organic Smorgasbord

Biennial meeting celebrates the breadth of cutting-edge research in organic chemistry

by Carmen Drahl
July 13, 2009 | A version of this story appeared in Volume 87, Issue 28

Sweet Scaffold
Cartoon of natural polysaccharide (left) and of synthetic tetrasaccharide polymer (right).
Cartoon of natural polysaccharide (left) and of synthetic tetrasaccharide polymer (right).

Language interpretation, building construction, and sports analysis usually don’t come up at chemistry meetings. But they’re apt metaphors for strategies presented to the more than 700 organic chemists at the 41st Biennial National Organic Chemistry Symposium (NOS), held at the University of Colorado, Boulder’s eco-conscious campus on June 7–11.

NOS, first established in 1925, is sponsored by the American Chemical Society’s Division of Organic Chemistry. Organizers Mukund P. Sibi of North Dakota State University and Tarek Sammakia and Andrew J. Phillips of CU Boulder told C&EN that NOS is known for fostering an intimate environment. “This is a big conference, but there is a very personal feel to it,” Phillips said. That was especially true at the poster sessions, where eminent chemists mingled with students and young scientists in front of nearly 400 posters.

In line with tradition, an evening session feted the winner of the ACS Roger Adams Award in Organic Chemistry. This year’s winner, Andrew Streit­wieser of the University of California, Berkeley, said he was “awed and humbled” to be joining the distinguished list of Adams awardees. Streitwieser shared how his early love of theoretical chemistry led to experimental and computational research on, among other things, the chemistry of the carbon-lithium bond (C&EN, March 2, page 52).

Although symposium attendance was down slightly this year compared with previous years, that didn’t dampen attendees’ enthusiasm for organic chemistry and its ability to provide tools for tackling tough problems in a broad range of areas, Sibi noted. The following meeting highlights, taken from the lineup of 13 invited lecturers, demonstrate that breadth.

Sugary Tools Dissect Neurons’ Chatter

Before attempting to read a sentence or a novel in a foreign language, it helps to first grasp some grammar and vocabulary for the language in question. Linda Hsieh-Wilson and her group at California Institute of Technology are doing their part to demystify a decidedly tricky tongue—that of the nervous system. Researchers are eager to understand communication in the nervous system because it underpins nerve growth, recovery from injuries, and more.

It helps that Hsieh-Wilson’s team is fluent in carbohydrate chemistry because sugars 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 polysaccharides in the chondroitin sulfate (CS) class. Hsieh-Wilson’s team is trying to comprehend how the structures of specific CS carbohydrates relate to their function.

The trouble with understanding the role of CS polysaccharides in neurobiology is that they are highly complex, with the sulfate groups arranged in diverse patterns on the sugar scaffold, Hsieh-Wilson says. Understanding the message a complex polysaccharide sends to the nervous system is like reading a set of instructions without any familiar words or phrases.

The team started by trying to figure out what some of the “words” in the CS language mean. To do that, they made defined disaccharides and tetrasaccharides with sulfate groups positioned at precise spots along the carbohydrate backbone. They learned that a specific three-dimensional pattern of sulfates in a sugar they call chondroitin sulfate-E acts as a recognition element, binding to growth factors in the brain and stimulating neuronal growth.

Somewhat paradoxically, CS polysaccharides are also implicated in inhibiting neuronal growth after an injury. Although short sugar chains worked just fine in the team’s neuronal growth studies, the chains didn’t seem to have much effect in growth inhibition assays. So the group sought a way to access longer polysaccharide structures. It’s tough to make such sequences, but Hsieh-Wilson’s team found a way around the problem. The researchers mimicked the activity of longer CS polysaccharides by making synthetic polymers that were decorated with defined CS di- or tetrasaccharide motifs along the polymer chain (J. Am. Chem. Soc. 2008, 130, 2959).

Catalyst Conundrum
The active form of this catalyst is in equilibrium with a catalytically inactive form. Adding more substrate (orange) pushes the equilibrium back toward the inactive species, thereby slowing the reaction rate.
The active form of this catalyst is in equilibrium with a catalytically inactive form. Adding more substrate (orange) pushes the equilibrium back toward the inactive species, thereby slowing the reaction rate.

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, Hsieh-Wilson 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.

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 mastered that second step—selective oxidation in complex settings. Despite a flurry of research in converting C–H bonds into C–O bonds, it isn’t easy to figure out where to start functionalizing a terpene skeleton, which can lead to a highly frustrating research endeavor.

Chen and Baran started their work by developing a framework to ease that frustration. The result was a modified approach to retrosynthetic analysis—a thought process for planning an organic synthesis—that might be better suited to the terpene challenge. “The beauty of retrosynthetic analysis is it gives people a framework, a basis to begin,” Baran says.

Chen and Baran developed something they call a retrosynthetic pyramid. The apex of the pyramid houses a highly oxidized terpene structure. Each step down the pyramid works backward to progressively less oxidized compounds. Eventually, the lowest oxidized members are reached, and those compounds form the pyramid’s bottom level. From those options on the bottom, Chen and Baran figured out the most logical place to start their synthesis. “Instead of making disconnections at specific bonds, we take a more holistic approach and disconnect to yield sets of compounds with equivalent oxidation states,” Baran says.

Read more symposium coverage on C&EN’s blog, “C&ENtral Science,” at

Chen demonstrated the utility of that framework experimentally by synthesizing a family of terpenes called the eudesmanes. She first constructed the carbon skeleton and then built atop that sturdy foundation with a series of site-selective carbon-hydrogen oxidations, notably one developed in the Baran group. A carbamate group attached to the eudesmane skeleton directed several key transformations.

The eudesmane study lays out a potential strategy for tackling terpene classes to come, Baran says. For instance, the tactics for building eudesmane might one day serve as a primer for constructing the terpene equivalent of the Taj Mahal: Taxol.

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 point someone will bust out a Telestrator to analyze a play by doodling onscreen. Telestrator-aided commentary helps viewers understand how a complicated play helps a team reach a goal and can even serve as a critique when something goes awry. Melanie S. Sanford also believes that breaking down a complex process and analyzing each player’s moves is a great way to understand what’s going on and to make something that’s already good even better. Except that Sanford deals with maneuvers on the molecular scale—not on the gridiron.

At NOS, Sanford, a chemist at the University of Michigan, Ann Arbor, proposed a mechanistic play-by-play for a palladium-catalyzed reaction that 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 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 catalyst. 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 containing two molecules of substrate.

To reach the active complex, “you lose two equivalents of the substrate, and that’s where this inverse order in substrate comes from,” Sanford says. The third equivalent of substrate gets lost via an interaction with the oxidant, she adds.

Now that they understand what’s going on, Sanford and Deprez have two ideas for improving the reaction: find a way to make the monometallic form of the catalyst catalytically active or find a way to keep the catalyst in its bimetallic, active form. They’d like to obtain the X-ray structure of the bimetallic species and determine whether similar intermediates are involved in other reactions. The active form of the catalyst is one of a growing group of bimetallic species that play key roles in transition-metal catalysis (C&EN, June 8, page 10).

Additional nuances remain to be worked out, Sanford notes. 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 qualities of the reactions to be understood, further mechanistic play-by-plays are surely still to come.


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