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Synthesizing Complex Natural Molecules with Carbon-Hydrogen

Collaborative efforts result in sophisticated C-H functionalization, enabling new frontiers in complex organic synthesis

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Chemists synthesized a highly complex natural molecule through a revolutionary strategy of functionalizing normally inert carbon-hydrogen (C-H).

Science published the breakthrough led by chemists at Emory University and Caltech. The work is the most dramatic example yet of a sequence of C-H functionalization reactions selectively transforming low-cost materials into complex building blocks of organic chemistry.

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Ten of the steps involved in their synthesis of cylindrocyclophane A -- a natural compound with antimicrobial properties -- involved C-H reactions.

"It's by far the most complex natural product we have made using our method," says Huw Davies, Emory professor of chemistry and co-corresponding author of the paper. "This is a game changer. We're doing chemistry on C-H bonds that formerly would have been considered as unreactive. And we've shown how we can orchestrate a suite of 10 C-H functionalization steps, targeting a single C-H bond at a time in a specific sequence."

"This work moves the field forward by showing the power of C-H functionalization," adds Brian Stoltz, professor of chemistry at Caltech and co-corresponding author of the paper. "It will open people's eyes to the possibilities of using these very selective and unusual transformations in a really complex setting."

First author is Aaron Bosse, who did the work as an Emory PhD student. Bosse has since graduated and is now a medicinal chemist at Takeda Pharmaceuticals in Cambridge, Massachusetts.

A major transformation in organic synthesis

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The work marks a capstone achievement for the $40 million National Science Foundation Center for Selective C-H Functionalization (CCHF), which was founded at Emory in 2009 as an NSF Center for Chemical Innovation. Directed by Davies, the CCHF grew to encompass 25 professors from 15 universities across the United States. The center also built global connections in Germany, Japan, South Korea and the U.K.

The center led a major transformation in organic synthesis, opening new chemical space for exploration.

"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 sites. It opens the possibility for synthesizing materials that are completely different from anything we've known."

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

C-H functionalization flips this model, designing tools to get reactions to occur at C-H bonds.

Changing the culture of a field

To achieve such an ambitious goal, the CCHF first had to catalyze a new culture within the field, breaking down barriers between labs and institutions to collaborate across specialties.

"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. We built a culture with the expectation that if you hear an interesting idea you think, 'How can I contribute in a collaborative way?' That can lead to a much more powerful impact than just focusing on your own specialty."

In addition to speeding up discovery, the collaborative spirit was fun.

"It's been transformative," Stoltz says. "We got really comfortable working with one another, presenting new ideas freely and openly, which was liberating. It's become one the most enjoyable experiences of my career."

A new way of teaching

That openness also led to changes in how organic synthesis is taught. Rather than just learning the techniques of one lab and one professor, students gain an array of expertise in fine chemicals development, materials science and drug development through collaborations -- including exchange programs between institutions.

Students also regularly present during virtual symposia, learning to explain their research and ideas across specialties and to think collaboratively.

In fact, a virtual symposium in 2015 sparked the collaboration that led to the current Science paper.

Kuangbiao Liao, an Emory PhD student who has since graduated and gone on to launch an organic synthesis company in Guangzhou, China, described new dirhodium catalysts for C-H functionalization with unprecedented site selectivity.

That breakthrough developed by the Davies lab eventually resulted in a Nature paper.

The new catalysts streamlined the process of C-H functionalization by eliminating the need for introducing a directing group to 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.

The lock-and-key method of the catalysts also controls the 3D shape of the resulting molecules. This architecture is particularly vital to the development of drug molecules since shape can influence their effects on biological molecules.

Combining forces

While the Davies lab primarily specializes in developing methodologies for C-H functionalization, the Stoltz lab primarily specializes in synthesizing complex molecules.

Stoltz immediately saw cylindocyclophane A as a good candidate to apply this new chemistry.

"The features of the molecules that the Emory group was making with the new catalysts had similar features to cylindocyclophane," he says. "The structures weren't a perfect match but they were close."

Within days, the Davies and Stoltz labs began working together on the quest to synthesize this complex compound in a completely new way.

As the project developed and the ideas were refined it became clear that it was a chance to highlight the impact of C-H functionalization by building the whole synthesis around different strategies developed through the CCHF.

The expertise of co-author Jin-Quan Yu, a chemist at the Scripps Research Institute, was brought in to expand the repertoire of C-H methods that could be applied to the synthesis.

A human story

Scott Virgil, a chemistry lecturer at Caltech, is another co-author of the paper.

In addition to the faculty from three research institutions, the project's co-authors include seven students spanning those institutions. Bosse mentored Camila Suarez, who was an Emory sophomore at the time the project launched in 2015 and continued working on it after she graduated from Emory and became a PhD student at Caltech. The other student researchers include Liam Hunt, Tyler Casselman, Elizabeth Goldstein and Austin Wright from Caltech; and Hojoon Park from the Scripps Research Institute.

As part of CCHF exchanges, Bosse spent time 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 do the synthesis, although some challenges remained."

Bosse graduated from Emory in 2022 but work on the synthesis continued.

Suarez, who bridged the project from beginning to end, helped with some final revisions on the Science paper.

"This past summer she performed some really key experiments that made the paper even stronger," Stoltz says.

"The stunning result was worth the effort," Davies says of the nearly decade-long project. "This is by far the most elaborate sequence of C-H functionalization reactions applied to a complex total synthesis. It will inspire people to think more broadly about the effective use of C-H functionalization."

"This goes beyond the chemistry," Stoltz adds. "It's a human story. Organic chemists working together across three institutions to synthesize a complex molecule is a very unusual thing."

Leading new era

While the Science publication marks a major milestone for the CCHF, work by the center has resulted in the publication of hundreds of papers, development of a toolkit of dozens of specialized reagents and catalysts, ongoing collaborations with private industry and the formation of numerous start-up companies.

With its foundational mission accomplished, the CCHF ceased operations as an NSF Center for Chemical Innovation in 2022.

The center's legacy lives on through an even bigger group of 45 professors from 29 universities working together through another Emory-led initiative known as the Catalysis Innovation Consortium (CIC). Pharmaceutical giants Novartis, AbbVie and Lilly are also part of the CIC.

"We built so much enthusiasm for collaborative research and sharing ideas through virtual meetings that we wanted to keep the momentum going," Davies says.

One focus of the CIC is to drive further advances in C-H functionalization through high-throughput experimentation and machine-learning techniques.

"Instead of experimenting with one flask and one reaction, high-throughput experimentation allows you to use a plate and experiment with hundreds of different reactions in one go," Davies explains. "We will use machine learning to analyze the resulting large datasets. That will allow us to develop predictive models for the optimum conditions to functionalize specific C-H bonds."

Just over 20 years ago, Davies notes, many chemists called the idea of selectively functionalizing C-H bonds "outrageous" and "impossible." Now, C-H functionalization is set to enter the mainstream.

"We've had a tremendous impact on developing C-H functionalization as both an academic discipline and for industry applications," Davies says. "We want to continue leading this new era in organic synthesis."

-Note: This news release was originally published by Emory University. As it has been republished, it may deviate from our style guide.

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