Chemical Bonds

Near the end of a four-month stay in Japan during summer 2014, Kathryn “Katie” Chepiga 18PhD hiked up Mount Fuji. An Emory graduate student of organic chemistry, Chepiga was immersed in an international research project through an exchange program of the National Science Foundation’s Center for Selective C-H Functionalization (CCHF). She and her Japanese counterpart at Nagoya University had made a significant finding involving a new method of organic synthesis. Now she wanted to cap her experience abroad by summiting Fuji, Japan’s highest mountain and an active volcano. 

“It was really cold, rainy, and foggy. We couldn’t see more than a few feet ahead of us,” Chepiga says of the first eight-hour leg of the hike. She was accompanied by Emory senior Michael Wade Wolfe 15C, who had recently arrived in Japan as part of the same CCHF exchange program.

The lack of visibility made all the pain and effort of hiking up one of the world’s most scenic peaks seem like a futile exercise. Soggy and freezing, they trudged on until they made it to a hiker’s communal way station where they could change into dry gear and get a few hours of sleep.

When they awoke before dawn, the rain had stopped and the fog had lifted. They continued their trek on a fresh blanket of snow. “The last few hundred meters, we walked single file, in a line of people wearing little headlamps,” Chepiga recalls. “It’s high altitude and slow going. It feels like you’re only moving a few steps every twenty minutes.”

Snow fell as they neared the crater rim. “You could see city lights peeking through the clouds below us,” Chepiga says. “It got more and more beautiful the higher we went. Then the sky turned from dark gray and black to orange and red. That sunrise was amazing. It was definitely worth the climb.”

Summiting Fuji was a walk in the park compared to the CCHF research that took Chepiga to Japan.  She joined forces with Atsushi Yamaguchi, a graduate student from Nagoya University, to demonstrate how a newer, more efficient strategy can be applied to synthesize natural compounds that hold potential medicinal benefits. “We ran into a lot of obstacles and dead ends, but we kept at it,” Chepiga says. “If you just keep putting one foot in front of the other, you know you can climb Mount Fuji. But in science you have to keep trying a lot of different approaches, even when you’re not sure you will achieve your goal. It’s much less certain and concrete.”

Their persistence paid off. In January, the Journal of the American Chemical Society (JACS) published their findings, showing how C-H functionalization speeds up synthesis of two promising marine alkaloids from a sea sponge, known as dictyodendrin A and F.

“We were able to cut the number of steps needed to synthesize these products nearly in half, compared to previous, more traditional methods,” Chepiga explains. “The ability to more efficiently synthesize them greatly improves the chances that they will be produced on a larger scale so that more can be learned about their biological properties and potential benefits.”

Mixing It Up: Kathryn Chepiga (above left) and Atsushi Yamaguchi (right) played trading spaces with their labs.

Previous research has found that dictyodendrin A inhibits telomerase, suggesting its potential for cancer chemotherapy. And dictyodendrin F inhibits an amyloid-cleaving enzyme, hinting at its potential to treat Alzheimer’s disease.

The students shared lead authorship of the JACS paper. Their professors and mentors are coauthors, including Kenichiro Itami and Junichiro Yamaguchi from Nagoya and Emory organic chemist and professor Huw Davies. 

“This paper shows the power of the global network the CCHF has developed,” says Davies, director of the center, which is based at Emory. “We hope this work serves as a model for others to emulate and to expand upon—both the new methods of doing chemical synthesis and the new ways for organic chemists to combine their expertise and collaborate, rather than compete.”

The graduate students completed the synthesis of the two products over the course of one year.

“It’s common for a total synthesis project to take four to six years,” Davies says. “It’s amazing that they achieved it in such a short time. Emory had one area of expertise needed to complete the project, and the University of Nagoya had the other area. Katie and Atsushi bridged cultures and continents and brought these two areas together.”

The project began in fall 2013, when Atsushi Yamaguchi traveled to Atlanta to spend three months working in the Davies lab. He brought with him an idea from the Itami lab in Nagoya—to apply C-H functionalization methods to synthesize dictyodendrins.

Traditionally, organic chemistry has focused on the division between reactive, or functional, molecular bonds and the inert, or nonfunctional bonds carbon-carbon (C-C) and carbon-hydrogen (C–H). The inert bonds provide a strong, stable scaffold for performing chemical synthesis on the reactive groups.  

C-H functionalization flips this model on its head: It bypasses the reactive groups and does synthesis at the inert C-H sites.

The CCHF is at the forefront of this major paradigm shift in organic chemistry. It brings together scientists from leading research universities across the United States, Asia, and Europe—as well as from private industry—with the aim of making organic synthesis faster, simpler, and greener.

At the same time, the center is preparing students for a new era of collaborative chemistry on a global scale. Undergraduates, graduate students, and post-doctoral fellows can participate in national and international exchanges, learning the techniques of other labs while bringing in new ideas of their own.  

When Yamaguchi arrived at Emory, he hit the ground running, Davies recalls. “The culture of our lab is very different from the way they work in Japan, but Atsushi just jumped right in and embraced it. He was very focused and extremely determined to learn all that he could and to make his project work.”

Chepiga shares a similar determination, as well as the desire to gain varied experiences. She entered Emory’s graduate program in chemistry in 2010, drawn by the exchange opportunities offered by the CCHF.

The center began with a network of top research universities across the United States when it launched in 2009. Since then, it has expanded through the National Science Foundation program Science Across Virtual Institutes (SAVI) to also include organic chemistry labs and research centers in Japan, Korea, England, and Germany.

“In organic chemistry, you might spend your whole PhD program just learning the techniques and expertise of one lab and one professor,” Chepiga says. “When I heard how the center was changing that concept, I wanted to be a part of it. I’m gaining a range of expertise and learning how to adapt to different lab settings. And I have a much bigger network of professors and students to bounce ideas off of when I run into a problem. It never feels like there is a dull moment in a project because we can come at it from so many different angles.”

Last spring, Chepiga traveled to Nagoya to help Yamaguchi complete the synthesis project. “I loved the cultural experience and working in a new environment,” she says. “I found the members of the Itami lab to be incredibly friendly and helpful.”

The challenge facing the two graduate students was to perform controlled, sequential functionalization of four C-H bonds on a pyrrole core—a basic, organic unit common in many medicinal compounds.  

The Itami lab specializes in C-H arylation, a process that converts a C-H bond into an elaborate structure needed for the synthesis. The Davies lab is specialized in using rhodium catalysts to directly insert a carbene fragment into C-H bonds, another critical step. “We definitely struggled at times,” says Chepiga of the problems involved. “We worked a six-day week, every week.” 

But her hosts also made sure she saw some of the beauty and diversity of Japan outside the lab. Most Sundays, Chepiga would take train or bus trips with colleagues to visit a scenic spot. “We saw wild baboons walking toward us in the snow,” Chepiga recalls of a trip to Kamicohi, known as the Japanese Alps. “Japan has incredible beauty and diversity. There is so much to see. And I’d look forward to getting back to the lab on Monday because the work was so exciting.”

Chepiga especially appreciated a custom of the lab members to greet each and every colleague daily. “It’s a good feeling to have forty people tell you ‘good morning.’ It’s a great way to start the day,” she says.

While her work at the Davies lab has focused on catalyst development and applications, the exchange project required Chepiga to learn new techniques for synthesis and for analyzing the products of small-scale reactions. “It reinvigorated me to learn so many new skills,” she says.  

The published results of the project open new possibilities for chemistry. “We’re hoping that other researchers will want to explore the potential therapeutic benefits of dictyodendrins A and F, now that the synthesis is more practical,” she says. “And we also hope that our synthesic methods can be applied more broadly to many other compounds with interesting biological properties.”

Combining the expertise of different labs not only boosted the pace of discovery, it also speeded up Chepiga’s academic career. She is on track to finish her PhD program within a few months, for a total of just four and a half years, and she has already secured a postdoctoral fellowship in Germany. 

“My experiences in Japan made me want to see even more of the world,” Chepiga says.