Numerous biological compounds exist as “diastereomers” — compounds that possess the same chemical framework yet exhibit distinct spatial configurations of their atoms. In certain instances, these minor structural variations can result in considerable alterations in the functions or chemical characteristics of the compounds.
For instance, the oncological medication doxorubicin can induce heart-related side effects in a small fraction of patients. Conversely, a diastereomer of the medication, referred to as epirubicin, which features a single alcohol group oriented differently, is far less harmful to cardiac cells.
“There are numerous instances like that in pharmaceutical chemistry where something that appears minor, such as the position of an isolated atom in space, may be truly significant,” states Alison Wendlandt, an associate professor of chemistry at MIT.
Wendlandt’s laboratory concentrates on developing innovative tools that can transform these compounds into various forms. Her team is also exploring analogous tools capable of converting a compound into a different constitutional isomer — a compound that has an atom or chemical group situated in a different location, although it shares the same chemical formula as the initial version.
“If you possess a target compound and aimed to synthesize it without such a tool, you would need to revert to the start and reconstruct the entire compound again to achieve the desired final arrangement,” Wendlandt explains.
These tools can also facilitate the creation of entirely new compounds that may be challenging or possibly unfeasible to synthesize using conventional chemical synthesis methods.
“We are concentrating on a wide range of selective transformations, with the objective being to create the most significant influence on how one might imagine synthesizing a compound,” she explains. “If you can enable access to the interconversion of molecular structures, you can then conceive entirely differently about how to construct a molecule.”
From mathematics to chemistry
Being the daughter of two geologists, Wendlandt was immersed in scientific pursuits from an early age. Both of her parents were employed at the Colorado School of Mines, and family vacations frequently involved visits to fascinating geological sites.
During high school, she found mathematics more intriguing than chemistry, subsequently enrolling at the University of Chicago with intentions of majoring in mathematics. However, she quickly reconsidered after confronting the complexities of abstract mathematics.
“I excelled in calculus and the type of mathematics required for engineering, but upon reaching college and encountering topology and N-dimensional geometry, I realized I lacked the aptitude for abstract mathematics. At that juncture, I became somewhat more receptive to exploring what I wanted to study,” she recalls.
Even though she believed chemistry was not to her liking, an organic chemistry class during her sophomore year shifted her perspective.
“I adored the problem-solving dimension of it. I possess a very poor memory, and I couldn’t memorize my way through the coursework, so I was compelled to actually learn it, and that was incredibly enjoyable,” she recollects.
As a chemistry student, she began her work in a laboratory focusing on “total synthesis,” a research domain that entails devising strategies to synthesize complex compounds, often of natural origin, from scratch.
Though she was passionate about organic chemistry, a laboratory mishap — an explosion that harmed a student in her lab and resulted in temporary hearing loss for Wendlandt — made her reluctant to continue down that path. When applying to graduate programs, she opted for a different branch of chemistry — chemical biology. She attended Yale University for a couple of years but soon realized that she did not enjoy that type of chemistry and departed after earning a master’s degree.
She spent several years working in a lab at the University of Kentucky before applying to graduate school once more, this time at the University of Wisconsin. There, she engaged in an organic chemistry lab, investigating oxidation reactions that could be utilized to produce pharmaceuticals or other valuable compounds from petrochemicals.
After completing her PhD in 2015, Wendlandt pursued a postdoctoral position at Harvard University, collaborating with chemistry professor Eric Jacobsen. During this period, she developed an interest in selective chemical reactions that yield a specific isomer and began researching catalysts capable of performing glycosylation — the incorporation of sugar molecules into other compounds — at designated sites.
Modifying molecules
Since joining the MIT faculty in 2018, Wendlandt has dedicated her efforts towards developing catalysts that can transform a compound into its mirror image or an isomer of the original.
In 2022, she and her students created a tool known as a stereo-editor, which can modify the arrangement of chemical groups around a central atom termed a stereocenter. This editor comprises two catalysts that cooperate to initially impart sufficient energy to detach an atom from a stereocenter, and then substitute it with an atom that has an opposing orientation. That energy infusion is provided by a photocatalyst, which converts absorbed light into energy.
“If you possess a compound with an existing stereocenter, and require the other enantiomer, typically you would need to restart and synthesize the other enantiomer entirely. However, this new technique attempts to interconvert them directly, thereby offering a perspective on molecules as dynamic entities,” Wendlandt remarks. “You could produce any three-dimensional configuration of that compound, and later, in a separate step, you could completely rearrange the 3D structure.”
She has also devised tools that can transform common sugars like glucose into various isomers, including allose and other sugars that are challenging to extract from natural origins, as well as tools that can generate new isomers of steroids and alcohols. Presently, she is exploring methods to convert six-membered carbon rings into seven or eight-membered variants, and to add, remove, or substitute certain chemical groups attached to these rings.
“I am focused on designing general tools that will enable us to interconvert static structures. This may involve relocating a specific functional group to another area of the compound entirely, or transforming large rings into smaller ones,” she states. “Rather than viewing molecules that we construct as fixed, we are now perceiving them as potentially dynamic structures, which could revolutionize our approach to synthesizing organic compounds.”
This methodology also paves the way for the creation of entirely new compounds that have yet to be discovered, Wendlandt asserts. This could prove advantageous, for instance, in developing drug molecules that interact with a target enzyme in precisely the correct manner.
“There is an immense realm of chemical space that remains unexplored, an unusual chemical space that simply has not been synthesized. This is partly due to a lack of interest, or because it is exceedingly difficult to produce that specific entity,” she notes. “These types of tools grant access to isomers that might not be easily synthesized.”