by Dan Weix and Zhidao Huang
A recent report in the journal Science from researchers in the UW-Madison Department of Chemistry represents a significant advance in making the types of molecules needed in drug development. Molecules with three-dimensional complexity are known to be better for drug development than flatter molecules, but accessing molecular complexity has historically been challenging. The work in this paper sets the stage for addressing this long-standing problem.
The synergy of teaching and scholarship
The breakthrough reported in this paper illustrates the interplay of teaching and scholarship at UW-Madison. Faculty member Dan Weix, while revisiting classical studies as part of teaching an advanced course to undergraduate and graduate students, was struck by the potential of a reaction known as “decarbonylation” to address the central challenge of creating more molecules with three-dimensional complexity. Translating this idea to reality took a team of researchers with varied training and the outstanding facilities available at UW-Madison: postdoctoral organometallic chemist Zhidao Huang, computational chemist Michelle Akana (Ph.D., ‘23), and X-ray crystallography expertise provided by Kyana Sanders (Ph.D., ’24).
The background and challenges
Methods to quickly form flat molecules are some of the most-used methods in drug development, but molecules with three-dimensional complexity usually perform better as drugs. Reactions that quickly make molecules with 3D complexity 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 the classic decarbonylation step.
The breakthrough and outlook
The team systematically studied the decarbonylation process and hit upon a catalyst with the right properties to favor decarbonylation, but disfavor other undesirable steps. By providing a new, convenient way to access the key intermediate, an alkylated nickel complex, from a common starting material pool, alkyl carboxylic acids, this study sets the foundation for rapid advances 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 19 Sep 2024. Vol 385, Issue 6715. pp. 1331-1337. DOI: 10.1126/science.abi4860