Leverage electron-rich Metal Carbenoids to Address Limitations in the Synthesis of Medium-sized Rings

With the support of the Chemical Synthesis Program of the Chemistry Division, Professor Tom G. Driver of the University of Illinois Chicago (UIC) is studying the development of new reactions to synthesize medium-ring molecules. Despite their established important bioactivity, this scaffold is underrepresented in pharmaceutical compound libraries because of the lack of synthetic methods for their construction. The goal of this project is to develop new metal-catalyzed processes that leverage and tame the reactivity of highly reactive metal carbenes to trigger new bond formation to create these important molecules. UIC is a designated Minority- and Hispanic Serving institution, and the hypothesis-driven nature of this project is well suited for the education of scientists at all levels. Professor Driver has tailored his research program to provide opportunities for students to advance in their professional development. The funded project also includes research experiences for high school students to inspire their pursuit of careers in STEM fields, and Chemistry Career Fair professional development activities to show the types of jobs and careers undergraduate- and graduate students can aspire to. Medium-sized carbocycles and heterocycles are critical structural motifs in pharmaceuticals and natural products. Despite their established use as scaffolds in drugs, medium-ring molecules remain underrepresented in pharmaceutical compound libraries, which is attributed to the shortage of synthetic methods to construct them. The experiments proposed with this proposal address gaps in state-of-the-art methods by exploiting the novel reactivity embedded in non-carbonyl stabilized metal carbene catalytic intermediates to develop new reactions that form seven- and eight-membered rings through the construction of C–C, C–S, C–O, and C–N bonds. Towards that end, our goals are: (1) to develop new metal-catalyzed cyclization-migration reactions of metal carbenes to construct medium-ring heterocycles by exploiting their unique reactivity with esters; (2) to develop new ring-expansion reactions of metal carbenes to construct all carbon medium-sized rings through a unique C–C bond activation mechanism; and (3) to leverage the reactivity of non-carbonyl-stabilized metal carbenes to participate in [2,3] rearrangements via ylides to enable synthesis of medium-sized heterocycles. The resulting medium-ring compounds are being added to UICentre for Drug Discovery’s novel small molecule library and submitted to our HTS facility for screening to initiate future collaborations. This project serves as a fertile ground for the training of students to advance in their scientific careers and hosting professional career development activities to meet the goals outlined by PCAST to transform and charge the STEM-student pipeline. 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.