A new report in the journal Science from researchers in the UW-Madison Department of Chemistry represents a significant advancement in making the types of molecules needed in drug development. Molecules with a more 3D shape are known to be better for drug development than flatter molecules, but accessing these types of molecules has historically been more challenging. The work in this manuscript sets the stage for fixing this long-standing problem.
The synergy of teaching and scholarship
The breakthrough reported in this manuscript illustrates the interplay of teaching and scholarship at UW-Madison. Faculty member Dan Weix, a global leader in the invention of new chemical reactions, was struck by the potential of decarbonylation to address the central challenge in creating more 3D molecules while revisiting classical studies as part of teaching an advanced course to undergraduate and graduate students. Realizing this idea took a team of researchers with varied training and the facilities available at UW-Madison: postdoctoral organometallic chemist Zhidao Huang, computational chemist Michelle Akana (PhD, ‘23), and X-ray crystallography by Kyana Sanders (PhD, ’24).
The background and challenges
Methods to quickly form flat molecules are some of the most-used methods in drug development, but more 3D molecules usually perform better as drugs. Reactions that quickly make more 3D molecules are not as efficient because they require specialized starting materials or form complex mixtures of products. Dan Weix’s group is known for inventing reactions that rely upon readily available starting materials and unusual mechanisms, but finding an approach that utilized abundant feedstocks and avoided mixtures required thinking about a new way to use an old step: decarbonylation.
The breakthrough and outlook
The team systematically studied the decarbonylation step and hit upon a catalyst that had the right mix of properties to favor decarbonylation, but disfavor other undesirable steps caused by the liberated carbon monoxide. With a new way to readily access the key intermediate, an alkylated nickel complex, from the a common starting material pool, alkyl carboxylic acids, this study sets the foundation for rapid advancements in 3D molecule synthesis.
Details about this study: “A decarbonylative approach to alkylnickel intermediates and C(sp3)-C(sp3) bond formation.” Zhidao Huang, Michelle E. Akana, Kyana M. Sanders, and Daniel J. Weix* (*corresponding author) Science 2024
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