With this award, the Chemical Synthesis Program of the Division of Chemistry is supporting the research of Professor Matthew Cook of the Department of Chemistry and Biochemistry at Montana State University. Professor Cook is studying new catalytic reactions that produce molecules containing a carbon atom bound to four other carbon atoms. Such carbons atoms are called "all-carbon quaternary centers". These carbons can possess a property known as "chirality" or "handedness". Chiral molecules, like human hands, are not superimposable on their mirror images. The two-handed forms of such molecules (like the left hand or the right hand) can be difficult to generate selectively. This is even more so in the case of compounds that bear all-carbon quaternary centers. Roughly 10% of the 200 top selling pharmaceuticals contain chiral all-carbon quaternary centers; however, none can be synthesized entirely in a laboratory. Instead, they are formed from naturally occurring sources. Professor Cook addresses this problem by developing new palladium-catalyzed methods that can selectively form chiral, all-carbon quaternary centers with a preference for one handed form over the other. Professor Cook also works closely with Professor Neufeldt, also at Montana State University, to investigate the mechanism of theses reactions so they can be further improved and optimized. This project provides excellent preparation for graduate and undergraduate students in future careers in STEM fields, in either academia or industry. Professor Cook also works on an outreach program to introduce K-12 school students living in Montana's rural areas (including a large Native American population) to practical science and modern instrumentation, with the aim of fostering their interests in STEM subjects and improving their enrollment rates at college.
Professor Cook is exploring the use of new pi-allylic rearrangement chemistry to generate stereogenic all-carbon quaternary centers with high levels of stereoselectivity. He is adopting two approaches, both of which utilize N-alloc carbamates that undergo a decarboxylative rearrangement to generate the requisite stereocenter. These methods overcome the major challenge in pi-allyl chemistry in acyclic systems, efficiently controlling E/Z selectivity in the nucleophile. By utilizing N-alloc enamines, which are much more configurationally stable than their enolate analogs, geometric fidelity can be retained. This allow catalyst control to dictate the stereochemical outcome. Another strategy being pursued uses N-alloc ynamides, which generate ketenimines following a pi-allylic rearrangement. These ketenimine intermediates then undergo a subsequent sigmatropic rearrangement, nucleophilic addition, or a second pi-allylic rearrangement to generate an all-carbon stereocenter. These ketenimine intermediates are chiral but undergo epimerization, and are being used in dynamic kinetic resolution reactions. Detailed mechanistic studies of both of these reactions are being conducted experimentally and computationally in collaboration with Professor Sharon Neufeldt at Montana State.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.