A group of researchers from Caltech and Emory University has successfully synthesized a highly intricate natural molecule utilizing an innovative approach that activates typically nonreactive bonds known as carbon-hydrogen (C–H) bonds. This research introduces a new category of reactions that organic chemists can explore as they aim to produce natural products for pharmaceuticals, develop new materials, or create organic chemicals in more environmentally friendly 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.”
Traditionally, C–H bonds have been perceived as inert and nonreactive in organic chemistry because of their resilience, serving as robust frameworks for molecular structures. Chemical transformations have conventionally targeted more reactive functional groups instead. However, this innovative research flips the script, harnessing new catalysts alongside expertly designed transformations to enable reactions at C–H bonds.
The synthesis culminates in the creation of cylindrocyclophane A—a complex natural product with promising antimicrobial properties, synthesized from cost-effective materials through a series of ten C–H functionalization steps.
“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 was once barren [chemical] sites. It opens the possibility for synthesizing materials that are completely different from anything we’ve known.”
The project originated from the National Science Foundation (NSF)-supported Center for Selective C–H Functionalization (CCHF), established by Davies in 2009, which eventually brought together 25 professors from 15 universities across the U.S. and various global collaborations.
In 2015, a virtual symposium sparked the partnership that resulted in the new publication in Science. During that discussion, Kuangbiao Liao, who was a graduate student at Emory University at the time, presented novel types of catalysts known as dirhodium catalysts that facilitate C–H functionalization. These innovative catalysts simplified the C–H functionalization process by removing the necessity of adding a separate chemical, known as a directing group, to target a specific C–H bond.
Instead, the catalysts’ three-dimensional surfaces function like a lock and key, permitting only a specific C–H bond in a compound to engage with the catalyst and participate in the reaction. Recognizing the potential of this new chemistry for synthesizing cylindrocyclophane A, Stoltz promptly reached out to Davies via email, and within a few days, their laboratories initiated collaborative efforts to synthesize the compound using this new technique.
As the project progressed, the team discovered that it showcased the advantages of C–H functionalization by employing a range of strategies developed through the CCHF. Throughout the process, the team broadened the array of C–H methods applicable for the synthesis by involving co-author Jin-Quan Yu, a researcher at the Scripps Research Institute, known for his expertise in C-H oxidation catalysis and contribution to the new publication.
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 a very enabling technology that we weren’t aware was possible before.”
Journal reference:
- Aaron T. Bosse, Liam R. Hunt, Camila A. Suarez, Tyler D. Casselman, Elizabeth L. , Austin C. Wright, Hojoon Park, Scott C. Virgil, Jin-Quan Yu, Brian M. Stoltz, Huw M. L. Davies. Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization. Science, 2024; DOI: 10.1126/science.adp2425