Many biological molecules exist as "diastereomers" - molecules that have the same chemical structure but different spatial arrangements of their atoms. In some cases, these slight structural differences can lead to significant changes in the molecules' functions or chemical properties.
As one example, the cancer drug doxorubicin can have heart-damaging side effects in a small percentage of patients. However, a diastereomer of the drug, known as epirubicin, which has a single alcohol group that points in a different direction, is much less toxic to heart cells.
"There are a lot of examples like that in medicinal chemistry where something that seems small, such as the position of a single atom in space, may actually be really profound," says Alison Wendlandt, an associate professor of chemistry at MIT.
Wendlandt's lab is focused on designing new tools that can convert these molecules into different forms. Her group is also working on similar tools that can change a molecule into a different constitutional isomer - a molecule that has an atom or chemical group located in a different spot, even though it has the same chemical formula as the original.
"If you have a target molecule and you needed to make it without such a tool, you would have to go back to the beginning and make the whole molecule again to get to the final structure that you wanted," Wendlandt says.
These tools can also lend themselves to creating entirely new molecules that might be difficult or even impossible to build using traditional chemical synthesis techniques.
"We're focused on a broad suite of selective transformations, the goal being to make the biggest impact on how you might envision making a molecule," she says. "If you are able to open up access to the interconversion of molecular structures, you can then think completely differently about how you would make a molecule."
From math to chemistry
As the daughter of two geologists, Wendlandt found herself immersed in science from a young age. Both of her parents worked at the Colorado School of Mines, and family vacations often involved trips to interesting geological formations.
In high school, she found math more appealing than chemistry, and she headed to the University of Chicago with plans to major in mathematics. However, she soon had second thoughts, after encountering abstract math.
"I was good at calculus and the kind of math you need for engineering, but when I got to college and I encountered topology and N-dimensional geometry, I realized I don't actually have the skills for abstract math. At that point I became a little bit more open-minded about what I wanted to study," she says.
Though she didn't think she liked chemistry, an organic chemistry course in her sophomore year changed her mind.
"I loved the problem-solving aspect of it. I have a very, very bad memory, and I couldn't memorize my way through the class, so I had to just learn it, and that was just so fun," she says.
As a chemistry major, she began working in a lab focused on "total synthesis," a research area that involves developing strategies to synthesize a complex molecule, often a natural compound, from scratch.
Although she loved organic chemistry, a lab accident - an explosion that injured a student in her lab and led to temporary hearing loss for Wendlandt - made her hesitant to pursue it further. When she applied to graduate schools, she decided to go into a different branch of chemistry - chemical biology. She studied at Yale University for a couple of years, but she realized that she didn't enjoy that type of chemistry and left after receiving a master's degree.
She worked in a lab at the University of Kentucky for a few years, then applied to graduate school again, this time at the University of Wisconsin. There, she worked in an organic chemistry lab, studying oxidation reactions that could be used to generate pharmaceuticals or other useful compounds from petrochemicals.
After finishing her PhD in 2015, Wendlandt went to Harvard University for a postdoc, working with chemistry professor Eric Jacobsen. There, she became interested in selective chemical reactions that generate a particular isomer, and began studying catalysts that could perform glycosylation - the addition of sugar molecules to other molecules - at specific sites.
Editing molecules
Since joining the MIT faculty in 2018, Wendlandt has worked on developing catalysts that can convert a molecule into its mirror image or an isomer of the original.
In 2022, she and her students developed a tool called a stereo-editor , which can alter the arrangement of chemical groups around a central atom known as a stereocenter. This editor consists of two catalysts that work together to first add enough energy to remove an atom from a stereocenter, then replace it with an atom that has the opposite orientation. That energy input comes from a photocatalyst, which converts captured light into energy.
"If you have a molecule with an existing stereocenter, and you need the other enantiomer, typically you would have to start over and make the other enantiomer. But this new method tries to interconvert them directly, so it gives you a way of thinking about molecules as dynamic," Wendlandt says. "You could generate any sort of three-dimensional structure of that molecule, and then in an independent step later, you could completely reorganize the 3D structure."
She has also developed tools that can convert common sugars such as glucose into other isomers, including allose and other sugars that are difficult to isolate from natural sources, and tools that can create new isomers of steroids and alcohols. She is now working on ways to convert six-membered carbon rings to seven or eight-membered rings, and to add, subtract, or replace some of the chemical groups attached to the rings.
"I'm interested in creating general tools that will allow us to interconvert static structures. So, that may be taking a certain functional group and moving it to another part of the molecule entirely, or taking large rings and making them small rings," she says. "Instead of thinking of molecules that we assemble as static, we're thinking about them now as potentially dynamic structures, which could change how we think about making organic molecules."
This approach also opens up the possibility of creating brand new molecules that haven't been seen before, Wendlandt says. This could be useful, for example, to create drug molecules that interact with a target enzyme in just the right way.
"There's a huge amount of chemical space that's still unknown, bizarre chemical space that just has not been made. That's in part because maybe no one has been interested in it, or because it's just too hard to make that specific thing," she says. "These kinds of tools give you access to isomers that are maybe not easily made."
