the paper that was eventually published in Science.
Researchers have successfully created a complex natural molecule by revolutionizing the process of modifying typically stable carbon-hydrogen (C-H) bonds.
The scientific journal Science recently published this significant advancement, which was driven by chemists from Emory University and Caltech. This research showcases the most significant achievement yet in a series of C-H functionalization reactions that efficiently convert inexpensive materials into intricate components of organic chemistry.
The synthesis of cylindrocyclophane A — a natural molecule known for its antimicrobial properties — involved ten distinct C-H reactions.
“This is the most intricate natural product we’ve synthesized using our approach,” stated Huw Davies, a professor of chemistry at Emory and a co-corresponding author of the study. “It’s a breakthrough. We are now engaging with C-H bonds that were previously thought to be unreactive, and we’ve developed a method to conduct a series of 10 C-H functionalization reactions, each targeting a specific C-H bond in a precise order.”
“This research propels the field forward by demonstrating the immense potential of C-H functionalization,” added Brian Stoltz, a chemistry professor at Caltech and co-corresponding author. “It will broaden perspectives on what can be achieved through these highly selective and unusual transformations in complex scenarios.”
Aaron Bosse, who conducted this research as a Ph.D. student at Emory, is the first author. He has since completed his degree and is now working as a medicinal chemist at Takeda Pharmaceuticals in Cambridge, Massachusetts.
A significant leap in organic synthesis
This achievement represents a pivotal milestone for the $40 million National Science Foundation Center for Selective C-H Functionalization (CCHF), established at Emory in 2009 as part of the NSF Center for Chemical Innovation. Under Davies’s direction, the CCHF has expanded to include 25 faculty from 15 universities across the U.S., while also fostering international collaborations in countries like Germany, Japan, South Korea, and the U.K.
The center initiated a major overhaul in organic synthesis, creating new avenues for chemical research.
“It’s akin to a farmer being able to cultivate crops in the desert or in Antarctica,” explains Davies. “C-H functionalization offers a groundbreaking approach for chemists to produce materials in areas previously viewed as unproductive. It paves the way for creating substances that are entirely novel to us.”
Traditionally, organic chemistry has concentrated on the distinction between reactive functional bonds and inert non-functional bonds, such as carbon-hydrogen (C-H). These stable bonds served as a robust framework for synthesizing chemical compounds from reactive groups.
The introduction of C-H functionalization alters this traditional model, developing techniques that allow reactions to occur at C-H bonds.
Transforming the field’s culture
For such an ambitious objective to be realized, the CCHF first needed to cultivate a new collaborative culture within the discipline, bridging gaps between laboratories and institutions to foster interdisciplinary partnerships.
“Before the CCHF, organic chemistry was quite isolated,” notes Stoltz. “Researcher typically guarded their ideas, sharing their findings with outsiders only after verifying results.”
“We all recognized the significant challenge at hand,” remarks Davies, “and built the trust necessary to merge our talents instead of competing against one another. We established a culture in which, upon hearing an intriguing idea, the thought would be, ‘How can I collaborate effectively?’ This approach can lead to much greater innovation than solely focusing on individual strengths.”
Beyond accelerating breakthroughs, the spirit of cooperation made the process enjoyable.
“It’s been a transformative experience,” Stoltz confirms. “We became comfortable collaborating, exchanging ideas openly, which was liberating for everyone involved. It’s emerged as one of the most satisfying experiences of my career.”
A new educational approach
This openness also influenced how organic synthesis is taught. Instead of merely acquiring the techniques of a single lab and professor, students now receive a diverse education encompassing various expertise in fine chemical development, materials science, and drug development through collaborations that include institutional exchange programs.
Students frequently present their work during virtual symposia, enhancing their skills in communicating their research and ideas across various specializations and engaging in collaborative thinking.
In fact, a virtual symposium held in 2015 sparked the collaboration that culminated in the current publication in Science.
Kuangbiao Liao, a former Emory Ph.D. student who has since founded an organic synthesis company in Guangzhou, China, introduced innovative dirhodium catalysts for C-H functionalization with remarkable site selectivity.
That advancement from the Davies lab ultimately led to a publication in Nature.
The new catalysts simplified the C-H functionalization process by removing the requirement for a directing group to identify a specific C-H bond. The unique three-dimensional structure of the catalysts essentially functions as a lock and key, allowing only one specific C-H bond within a compound to interact with the catalyst and undergo a reaction.
This lock-and-key mechanism also dictates the 3D structure of the resulting molecules. This aspect is particularly crucial in drug development, as the shape can significantly affect interactions with biological molecules.
Strength in unity
While the Davies lab primarily focuses on developing C-H functionalization methods, the Stoltz lab specializes in the synthesis of intricate molecules.
Stoltz immediately recognized cylindrocyclophane A as an excellent candidate for applying this novel chemistry.
“The characteristics of the molecules produced by the Emory team using the new catalysts showed similarities to cylindrocyclophane,” he mentioned. “Although they weren’t identical, they were quite similar.”
Within a matter of days, the Davies and Stoltz labs commenced a collaborative effort to synthesize this complex compound using a completely novel approach.
As the project evolved and the ideas were refined, it became evident that this was an opportunity to illustrate the impact of C-H functionalization by constructing the entire synthesis around diverse strategies established through the CCHF.
Co-author Jin-Quan Yu, a chemist at the Scripps Research Institute, contributed his expertise to broaden the range of C-H methods applicable to the synthesis.
A narrative of collaboration
Scott Virgil, a chemistry lecturer at Caltech, is another co-author of the paper.
In addition to faculty members from three research institutions, the project features contributions from seven students representing these institutions. Bosse mentored Camila Suarez, who was an Emory sophomore when the project began in 2015 and remained involved after graduating from Emory and pursuing her Ph.D. at Caltech. Other student contributors included Liam Hunt, Tyler Casselman, Elizabeth Goldstein, and Austin Wright from Caltech; as well as Hojoon Park from the Scripps Research Institute.
As part of CCHF exchange initiatives, Bosse spent time working in the Stoltz lab at Caltech.
“He collaborated with our students to make a final push for the project,” Stoltz said. “This effort laid the groundwork for the synthesis, despite some remaining challenges.”
Bosse graduated from Emory in 2022, but work on the synthesis continued.
Suarez, who was a vital link in the project from inception to completion, assisted with final adjustments on the manuscript that ultimately got published in Science.
“This past summer, she conducted some crucial experiments that enhanced the quality of the paper,” Stoltz remarks.
“The remarkable outcome justifies the long-term effort,” Davies comments on the nearly ten-year project. “This is undoubtedly the most intricate series of C-H functionalization reactions applied in a complex total synthesis. It will encourage others to consider more innovative uses of C-H functionalization.”
“This story goes beyond mere chemistry,” Stoltz adds. “It’s a tale of human collaboration. Organic chemists from three different institutions coming together to synthesize a complex molecule is quite rare.”
Pioneering a New Era
The publication in Science represents a significant achievement for the CCHF, which has led to the release of hundreds of research papers, the creation of a toolkit with numerous specialized reagents and catalysts, continuous partnerships with private companies, and the establishment of several start-ups.
Having accomplished its core mission, the CCHF concluded its role as an NSF Center for Chemical Innovation in 2022.
The center’s legacy continues with a larger consortium of 45 professors from 29 universities collaborating under the Emory-led Catalysis Innovation Consortium (CIC). Notable pharmaceutical companies like Novartis, AbbVie, and Lilly are also involved in the CIC.
“We generated great enthusiasm for collaborative research and sharing ideas through virtual meetings, and we wanted to maintain that momentum,” Davies explains.
One of the CIC’s goals is to advance C-H functionalization using high-throughput experiments and machine learning techniques.
“High-throughput experimentation enables us to test hundreds of different reactions simultaneously instead of just one, using a reaction plate,” Davies elaborates. “We will leverage machine learning to analyze the vast datasets generated, helping us create predictive models for optimal conditions to functionalize specific C-H bonds.”
Davies points out that just over two decades ago, many chemists considered the idea of selectively modifying C-H bonds “outrageous” and “unfeasible.” Nowadays, C-H functionalization is on the verge of becoming mainstream.
“We have significantly influenced the development of C-H functionalization as both an academic pursuit and for industrial uses,” Davies concludes. “We are committed to leading this new chapter in organic synthesis.”