Expanding the Synthetic Applications of Enol Esters and Their Epoxide Derivatives

With the support of the Chemical Synthesis Program of the Division of Chemistry, Professor Gregory Friestad of the Department of Chemistry at University of Iowa is developing new ways to create structurally complex small molecules from simple hydrocarbon precursors. The goal of this research is to exploit transition metal-catalyzed additions to alkynes and epoxidations to access enol ester epoxides and related compounds, and to develop novel ring-opening chemistry of enol ester epoxides to prepare densely functionalized building blocks more efficiently for synthesis. The project lies at the interface of organic, medicinal, and natural products chemistry, and it will provide an excellent setting for graduate and undergraduate education in synthetic chemistry and well-trained chemists for academic and industry workforce development. Ruthenium-catalyzed addition of carboxylic acids to alkynes and epoxidation of enol esters have great potential, but thus far have seen limited synthetic application. This project will develop asymmetric catalysis via kinetic resolution of enol esters derived from racemic alkynes, desymmetrization of enol esters derived from achiral alkynes, and group selectivity of intramolecular addition to diynes. The resulting aldehyde-derived 1,2-disubstituted acyclic enol esters, cyclic enol esters, and 1,1-disubstituted enol esters will be employed as substrates for asymmetric epoxidation to generate enol ester epoxides. These are mostly unexplored reactive compounds that offer potential for stereocontrolled and step-economic ring-opening reactions to generate highly functionalized chiral small molecules with broader impacts in medicinal and natural products chemistry. This project will test the scope of the reactions with both the 1,2-disubstituted and 1,1-disubstituted enol ester epoxides. Useful alpha-substituted aldehydes and alpha-haloalkyl esters will be formed. Reactivity and stereoselectivity aspects of carbon-carbon bond constructions of both enol ester epoxides and alpha-haloalkyl esters will also be developed, using carbon nucleophiles, carbon-centered radicals, and organotransition metal compounds to generate diverse 1,2-diol structures. 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.