This project seeks to develop donor-acceptor cyclopropanes as simple, but broadly useful building blocks for a range of formal [3+2] cycloaddition reactions. Intercepting Lewis acid activated malonyl cyclopropanes with aldehydes, ketenes, cyclic imines, nitriles, and azo compounds will be studied to deliver tetrahydrofurans, cyclic enol ethers, bicyclic pyrrolidines, pyrrolines, and pyrazolidines, respectively. The project could lead to the rapid access to key substructures of naturally occurring biologically active compounds like the cladiellin diterpenes.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Jeffrey Johnson of the Department of Chemistry at the University of North Carolina at Chapel Hill. Professor Johnson's research efforts are broadly in the area of chemical synthesis. The chemistry to be developed under the aegis of this grant is projected to positively impact the efficiency with which structurally interesting heterocyclic structures may be prepared in the laboratory. Such substructures are ubiquitous in biologically active natural products and medicinal agents.
The larger context for this particular NSF grant is the efficiency with which small molecule drug candidates can be prepared. A bottleneck in the drug discovery process is often simply what compounds can be accessed with available methods. Heterocyclic structures (that is, those ring structures containing both carbon and nitrogen or oxygen atoms) are especially attractive targets that can be difficult to access. Our work has dramatically expanded the tool kit that is available for the creation of new heterocyclic structures with precisely defined three dimensional arrangements of atoms. This control of 3D relationships (stereochemistry) is often critical for bioactivity and we have achieved this through careful development of catalysts that successful guide the reactants through a single transition state. We have explored this question broadly, with the goal of using our fundamental understanding of these reactions to guide the development of as many variants as possible. This has had the result of broadening the subset of reactions, which are the ultimate output of this grant, that are available to the scientific community at large. This project has provided an excellent example of how fundamental research can lead to practically useful outcomes. In particular, we were interested in the microscopic details of how these annulation reactions proceed and how we could use that information to design new and useful reactions. The unusual mechanistic details that emerged paved the way for numerous advances in the target area.
