Breaking Carbon–Hydrogen Bonds to Make Complex Molecules

A team of scientists led by Caltech and Emory University has synthesized a highly complex natural molecule using a novel strategy that functionalizes normally nonreactive bonds, called carbon–hydrogen (C–H) bonds. The work demonstrates a new category of reactions that organic chemists can consider as they work to create natural products that could be used in pharmaceuticals or new materials, or to produce organic chemicals in more sustainable ways.

"This work moves the field forward by showing the power of C–H functionalization," says Brian Stoltz, the Victor and Elizabeth Atkins Professor of Chemistry at Caltech, a Heritage Medical Research Institute Investigator, and co-corresponding author of a paper describing the new method in the journal Science. "I think this paper shows that you can use these very selective, very interesting, and very unusual transformations even in a complex setting where you have a lot of competing reactive positions. It just opens up a lot of chemistry that you wouldn't have considered before."

Typically, in organic chemistry, C–H bonds are considered nonreactive, or inert. Such bonds are difficult to break and usually provide a strong, stable scaffold for molecules; chemical transformations, meanwhile, typically involve more reactive groupings of chemicals known as functional groups. The new work flips this model by using a number of new catalysts and carefully designed transformations that allow a series of reactions to occur at C–H bonds. The total synthesis, which involves a total of 10 C–H functionalization steps, ultimately produces a complex molecule called cylindrocyclophane A, a natural product with antimicrobial properties starting from low-cost materials.

"It's by far the most complex natural product we have made using our method," says Huw Davies, a professor of chemistry at Emory and co-corresponding author of the paper.

The new method creates new possibilities for synthesizing previously unavailable chemicals. "It's like a farmer being able to grow crops in the desert or in Antarctica," Davies explains. "C–H functionalization represents a whole new way for chemists to synthesize material in what were once barren [chemical] sites. It opens the possibility for synthesizing materials that are completely different from anything we've known."

The work grew out of the National Science Foundation (NSF)-funded Center for Selective C–H Functionalization (CCHF) led by Davies, which began in 2009 and eventually included 25 professors from 15 American universities with additional global connections. The center, Stoltz and Davies say, has encouraged a new collaborative culture within the field.

"Prior to the CCHF, organic chemistry was really very insular," Stoltz says. "Individual investigators tended to covet their ideas. They would only present their findings to those outside of the lab when they had proven results."

"We all recognized the grand challenge before us," Davies says, "and developed the trust needed to combine our expertise rather than compete."

That collaborative spirit led to the sharing of project ideas and progress, regular team exercises in dreaming up novel syntheses, and virtual symposia, where students presented their research and ideas across specialties.

In 2015, such a virtual symposium sparked the collaboration that led to the new Science paper. During that talk, Kuangbiao Liao, then a graduate student at Emory University, described new types of catalysts known as dirhodium catalysts to drive C–H functionalization.

The new catalysts streamlined the process of C–H functionalization by eliminating the need to introduce a separate chemical with what is called a directing group that would target a specific C–H bond. Instead, the three-dimensional exteriors of the catalysts act like a lock and key, allowing only one particular C–H bond in a compound to approach the catalyst and undergo the reaction.

Stoltz immediately saw that this new chemistry had potential for the synthesis of cylindrocyclophane A. He shot Davies an email, and within days, the two labs began working to synthesize the compound using the new approach.

As the project developed, the team realized it provided the opportunity to highlight the impact of C–H functionalization by utilizing a variety of strategies developed through the CCHF.

Along the way, the team expanded the repertoire of C–H methods that could be applied to the synthesis by bringing in co-author Jin-Quan Yu, a chemist at the Scripps Research Institute, an expert in C-H oxidation catalysis and a co-author on the new paper. "The way we approach this molecule is with a very unusual strategy," says Stoltz, "and I don't think this ever would have happened without the multi-institutional aspect of this project."

In addition to the professors from three research institutions, other co-authors include students from each of those institutions. Lead author Aaron Bosse completed the work as a graduate student at Emory. There, he mentored Camila Suarez. Suarez, who was a sophomore when the project launched, continued working on the project after joining the Stoltz lab at Caltech as a graduate student in 2021.

As part of CCHF exchanges, Bosse spent a month at Caltech in the Stoltz lab.

"He worked with our students here to make a final push on the project," Stoltz says. "That set the final stage to make it possible to complete the synthesis, although some challenges remained."

This past summer, Suarez, who bridged the project from beginning to end, helped with the final push on the Science paper with Liam Hunt, a visiting graduate student at Caltech from the University of Auckland. "Cami performed really key experiments that made the paper even stronger," Stoltz says.

Over the summer, Suarez first had to produce the material to work with on campus and then tested many different reaction conditions to see if she could get one final chemical transformation to work in "one pot," using just one step. "And it did, which was really surprising and exciting," Suarez says. "This is the first case where you're able to do the Davies labs' rhodium-catalyzed C-H functionalization reaction twice in one step. I think this is very enabling technology that we weren't aware was possible before."

Reflecting on the work that she has been a part of for five years, Suarez, who is the president of Caltech's Diversity in Chemistry Initiative, says, "It's exciting that you can think of a very new way to break bonds. New reactions are being developed every single day, and they're becoming more robust, more powerful, more selective for very unusual and interesting transformations. Because of this innovation, we're able to think of new ways to synthesize natural products, and I feel like that's really important because organic chemistry is such a fundamental science that is involved in so many other sciences."

Additional authors on the paper, "Total synthesis of (-)-cylindrocyclophane A facilitated by C-H functionalization," are Hojoon Park from Scripps; Scott Virgil, director of the Caltech Center for Catalysis and Chemical Synthesis and a lecturer in chemistry at Caltech; and Tyler Casselman (PhD '23), Elizabeth Goldstein (PhD '20), and Austin Wright (PhD '20) who worked on the project while students at Caltech. The work was supported by the NSF, the National Institute of Health's National Institute of General Medical Sciences, the Heritage Medical Research Investigators Program, and the University of Auckland Doctoral Scholarship Award.

Emory University's release shares additional details of the project and the CCHF's legacy.