The biological activity displayed by small molecules is the result of their three dimensional interactions with molecular receptors. Therefore, the assembly of stereodefined units commonly found in bioactive compounds is central to the importance of synthetic chemistry in health-related research. Cyclobutanes are found in numerous compounds that display bioactivity and serve as excellent four-carbon synthetic building blocks. In order for the full potential of cyclobutane containing compounds to be realized, establishing general and efficient, and ultimately enantioselective, routes to their construction is crucial. Currently, available methods for the synthesis of four-membered carbocycles are limited as compared to decades-old routes to five- and six-membered analogs. This inhibits the exploration of this motif that is prevalent in biologically relevant molecules. Te long-term goal of this research is the development of general base-metal-catalyzed cycloaddition reactions that will provide rapid access to cyclobutanes for use as synthetic building blocks and in the construction of complex bioactive compounds. This research is based on the central hypothesis that base-metal catalysts offer unique advantages when coupled with redox-active ligands in order to facilitate transformations that are typically relegated to noble metal catalysis or are otherwise not feasible. Focus centers on three specific aims: (1) Devevlop general methods for the Fe-catalyzed intramolecular [2+2] cycloaddition of unactivated alkenes;(2) Develop general methods for the Fe-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes;and (3) Develop chiral catalysts for enantioselective base metal-catalyzed [2+2] cycloadditions. Our results will have a significant impact by providing rapid access to the largely untapped bioactivity-rich chemical space occupied by cyclobutanes and their derivatives while simultaneously expanding the understanding and utility of base metal catalysis for use in future reaction development.
The proposed research is relevant to public health because it provides a synthetic tool for the efficient synthesis of small molecule building blocks of biomedical importance using more sustainable and environmentally begin catalytic methods. The challenge of rapidly accessing these structures is a significant barrier to health related studies involving small molecules. We anticipate this research will facilitate the discovery of the next generation of small molecule therapeutics.