Chemists showcase power of pathbreaking method to make complex molecules

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Chemists have synthesized a highly complex natural molecule through a new strategy of functionalizing normally inert carbon-hydrogen (C-H). The journal Science has 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.

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."

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

A major transformation in organic synthesis

The work marks a capstone achievement for the 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.

"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," Davies explains.

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.

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.

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 Ph.D. 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.

Leading new era

One focus of the Catalysis Innovation Consortium (CIC), another Emory-led initiative, 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."

More information: Aaron T. Bosse et al, Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization, Science (2024). DOI: 10.1126/science.adp2425

Journal information: Nature , Science

Provided by Emory University