Puzzle-solving chemist helps boost synthesis of key bioactive compounds

A new approach to an established reaction boosts the ability to synthesize vinylic ethers—key building blocks for many molecules important to human health. The journal Organic Letters published the breakthrough, made by chemists at Emory University.

“Our method is easy to reproduce and is based on widely available and inexpensive compounds,” says San Pham, an Emory Ph.D. candidate and first author of the paper. “We can apply this method to make multiple natural products, including novel vinylic ethers.”

Her research improves the reliability, yield and generality of what is known as the Chan-Evans-Lam reaction. These enhancements greatly expand the reaction’s potential for the synthesis of complex, biologically active compounds for drug research.

“San Pham demonstrated that our new method works for several combinations of reactants, producing at least 15 new compounds that were previously unknown and would likely have been quite difficult to prepare using other known synthetic strategies,” says Frank McDonald, senior author of the paper and Emory professor of chemistry.

McDonald is also a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute of Emory University.

The McDonald lab explores new and improved methods for preparing organic compounds—particularly bioactive compounds that may become new pharmaceutical agents.

One area of interest is the synthesis of plasmalogens, a type of fat molecule found mainly in cell membranes. Preliminary studies suggest plasmalogens are involved in a range of beneficial biological activities, including anti-oxidation and anti-inflammation.

Vinylic ethers—which consist of an oxygen atom directly attached to a carbon atom that’s bonded to another carbon atom—are important synthetic intermediates for the synthesis of many bioactive compounds. A specific vinylic ether, with an alkene attached, is an intermediate for plasmalogen.

The few known methods for synthesizing vinylic ethers with an attached alkene, however, have limited their applications.

For nearly six years, the McDonald lab worked on developing a good way of making these key building blocks. One strategy was to try to leverage the Chan-Evans-Lam reaction. Developed 25 years ago, Chan-Evans-Lam is a cross-coupling reaction which forms a carbon-carbon bond with the aid of a copper catalyst.

While the reaction works well with simple reactants, the McDonald lab found it produced only low yields when linking two structurally complex reactants. That made the method impractical for the molecular synthesis needed to produce vinylic ethers.

“This reaction is also a little bit capricious,” McDonald says. “It’s not so easily reproducible and it didn’t seem to be fine tunable for our needs.”

Around two years ago, the lab nearly gave up on its quest to boost the potential of the Chan-Evans-Lam reaction. Then San Pham agreed to take on the project.

“I love solving problems, the more challenging, the better,” Pham says.

Even outside of the chemistry lab, she enjoys cracking puzzles. “I used to be addicted to sudoku, but I’ve moved on to the New York Times crossword,” she says. “I do it every day.”

Growing up in Saigon, Vietnam, Pham thought she wanted to be a doctor.

She received a full scholarship to Albion College in Michigan where she majored in biochemistry, with an eye toward medical school, and music. “I started playing piano when I was six,” she says. “I never want to lose my music. Music is the place I go to express myself.”

When she began studying for the Medical College Admission Test, Pham began rethinking her plan to become a physician. “I realized that medical school requires a lot of memorization and that doesn’t drive me intellectually,” she says. “It’s just not as fun for me.”

Meanwhile, she discovered that she loved doing research in a chemistry lab.

Pham came to Emory four years ago to pursue her Ph.D. and a career goal to become a research chemist. She found the ideal mentor in McDonald.

“He’s extremely knowledgeable but if he doesn’t know an answer he says so and then finds a way to get the answer,” Pham says. “He’s also nice and has a calm demeanor. I tend to be a bit intense, so it helps to be around someone really calm.”

“San has tremendous vitality and energy,” McDonald says. “In addition to being an outstanding scientist she is an avid soccer player and an astounding pianist.” He regularly attends campus recitals capping Pham’s music classes.

Pham’s insatiable curiosity is another key quality, he adds. “She enjoys a good detective hunt. And she doesn’t get discouraged easily.”

One problem the lab encountered with the Chan-Evans-Lam reaction is that the copper acetate catalyst is what is known as a dimer complex—two molecules bonded together. To catalyze the type of chain reactions the lab sought, the paired copper molecules needed to be broken into monomers, or single molecules.

“I started reading organic chemistry papers about breaking up this dimer, papers that weren’t even related to this reaction,” Pham says.

She spent months doing this research, scouring countless papers.

“Running random experiments is a waste of time and resources, so I’m strategic about my reaction design,” Pham explains. “Reading is how I develop strategic hypotheses for every reaction that I test.”

She found a paper reporting the use of a particular ligand—a catalyst activator that binds to a metal—to split the dimer into monomers.

She ran experiments using this new catalyst activator to synthesize the test compound.

The result yielded only 20% of the target compound, too low a percentage to make the method practical. Pham screened several more catalyst activators with similar chemical properties.

“No matter what I tried I couldn’t improve the yield beyond 50%, which is still not good enough,” she says. “I had hit a wall.”

Pham ran painstaking experiments to track and analyze every step in the process of the reaction to further understand its weaknesses. She pinpointed the step where the reaction produced an unwanted byproduct. That led to the insight that the catalyst needed to regenerate faster to favor the pathway to the target compound.

“At that point I was trying out oxygen gas as the reagent to regenerate the catalyst,” Pham says. “I was using a balloon to pump in the oxygen. It was challenging to ensure it was receiving enough.”

Pham dove back into the scientific literature, spending months reading through mechanistic papers about catalytic turnover and regeneration. She finally found a clue she needed: a paper citing the use of organic peroxide as a catalytic regenerator, rather than oxygen gas, to overcome a similar situation.

“I hit the jackpot, basically,” Pham says.

She ran more experiments with this final piece of the puzzle in place.

Pham’s enhancements sped up the reaction, reducing unwanted byproducts, and boosting the yield to 80% for the target compound.

She also achieved good yields for at least 15 different compounds new to the literature—demonstrating that her method applies to a wide range of complex structures important to drug discovery.

The McDonald lab is now set to build on Pham’s work to pursue its plasmalogen research.

“San’s improvements make this reaction a much more reliable and useful method,” McDonald says. “The new catalyst and reaction components are all relatively inexpensive and safe to use, and we hope other researchers will also explore its potential for synthetic applications.”

The paper describing the methods to achieve the breakthrough serves a broader purpose.

“I hope that when other people run into a problem working with similar substrates and are close to giving up,” Pham says, “they will read our paper and hit on a clue that helps them keep going.”