Science Spotlight: Bunt Lab

The laboratory of Burr Professor of Chemistry and Biochemistry and Chair of the Chemistry Department Rick Bunt is a small, unobtrusive room tucked about halfway down the north hall of the fifth floor in McCardell Bicentennial Hall. Pinned to a board outside the door are various published papers with long titles, and the lab is a visual maze of complicated instruments: oddly shaped glass tubes, rubber hoses, delicate looking electronics, small vials and large jugs of liquid scattered across shelves and benches.

For the layperson, the veil of visual complexity effectively disguises the important work that’s being done in the Bunt lab these days.

“We’re trying to understand how and why chemical reactions that form molecules with specific shapes work,” said Bunt.

His work at the College is an extension of the work he did in organic chemistry as a graduate student at Stanford University.

“I was trying to build successful chemical reactions and document the structure of the products,” said Bunt. “Now I’m trying to understand how those type of reactions work so that I can control a molecule’s three-dimensional shape when I synthesize it.”

Eric Roberts ’13 is Bunt’s sole thesis student this year and works directly with Bunt on his current project. He and Bunt are trying to understand the synthesis of molecules using a specific palladium-based catalyst, a molecule that makes the reaction work.

“Basically, you have a symmetric molecule that you’re trying to add another molecule to,” said Roberts. “And there are two possible outcomes, or enantiomers, that are non-super-imposable mirror images of each other, much like your left hand and right hand. And you can control which outcome you get with the palladium catalyst. We’re trying to understand how that control works.”

Think of the chemical reaction as the addition of thumbs to four-fingered gloves. The thumb piece can be sewn on to the glove to make either a left-handed glove or a right-handed glove. The final products are mirror images of each other, but not identical.

This type of work has direct applications in the pharmaceutical industry. When a drug is synthesized, there are several possible outcomes (enantiomers) in the chemical structure of the drug, but usually one of those structures is useful or applicable. An example is oseltamivir, a drug on the market with the trade name Tamiflu, which is used to treat symptoms of the flu. It was originally synthesized from shikimic acid, a chemical that is derived from Chinese anise seed. Due to the limited supply of Chinese anise in the world, pharmaceutical companies looked for a different way to synthesize the drug from scratch.

The problem is that the synthesis of the chemical needed to make Tamiflu has eight possible outcomes, and chemists are looking for one specific stereoisomer, or outcome. It’s as if there were eight possible types of gloves, and the chemists are looking for one specific version of the left-handed glove. To isolate the desired stereoisomer, chemists use a catalyst that only created that stereoisomer. The catalyst is like the needle and thread that sews the thumb piece to the glove, except in the case of oseltamivir, the needle and thread were only capable of sewing one type of glove, and that was the specific version of the left-handed glove.

Nathaniel Nelson ’11, who worked in Bunt’s lab for three summers and a full school year, helped explain this phenomenon.

“Compounds that are biologically active are usually stereochemically specific (right-handed or left-handed) to fit with the (right-handed or left-handed) enzymes working in the body,” he said. “For many reactions, if two enantiomers (one right-handed molecule and one left-handed molecule) are possible, you’ll get about 50 percent of each. If you’re making a drug, however, that needs to be only “right-handed,” say, then you waste 50 percent of your starting materials (presumably just throwing away the “left-handed” molecules). That waste is expensive and inefficient to generate. It means throwing out half of the products of a reaction. The key then, is to figure out how to synthesize only the desired stereoisomer (either the right hand or the left hand, but not both), using the right catalyst.”

That’s where the Bunt Lab comes in.

“Bunt’s work focuses on a type of catalyst formed when palladium coordinates with an organic ligand called PHOX ligand that favors one enantiomer over the other, [so] 90 percent “right-handed” molecules, 10 percent wasted “left-handed” molecules,” said Nelson.

Bunt is studying this specific set of reactions in depth to better understand the reaction’s mechanisms, and he’s making progress.

Several years ago when Nelson was working in Bunt’s lab, they had a curious and unexpected result.

“[We found] a single ligand which was totally inconsistent — sometimes forming products with huge preference for the ‘right-handed’ molecule, sometimes forming nearly 50 percent mixtures of the two and sometimes ending up somewhere in the middle … and we began to realize the reaction must be reversible,” said Nelson. This discovery was something no one had noticed before.

That’s where Roberts will pick up with his thesis work this year, trying to explain what Nelson characterizes as a “baffling irreversibility.” But he’s optimistic.

“I’m going to try to figure out how the catalyst breaks down, and hopefully begin to understand the mechanics of this reversible reaction,” Roberts said, acknowledging that it will be a big project. “Ideally 12-15 hours of lab work every week.”

Roberts wants to apply his chemistry major and economics and Spanish double minors at the interface of chemistry and business, which will take him out of the lab. However, what motivates him to put in such a significant chunk of time in the lab this year is an overwhelming sense of curiosity.

“It’s all about that moment of seeing into the universe and understanding fundamentally how it works, and being able to further that understanding with my own work and research,” he said.

Bunt, who has dedicated his life to chemistry, echoed this sentiment.

“I want to know how things work, why they work,” he said. “I’m mesmerized by the elegance of chemical synthesis.”