Stereoselective Synthesis of Biologically Relevant Heterocycles via Brønsted Acid Catalysis

PROJECT SUMMARY The goal of this proposal is to generate innovative strategies for the asymmetric preparation of different heterocyclic motifs, including N-containing compounds, that contain a chiral center. Realization of this goal is expected to benefit medicinal chemistry campaigns because >59% of FDA approved drugs include a nitrogen- containing ring system and >56% of FDA approved drugs contain a stereogenic center, the absolute configuration of which is often critical to the activity of the molecule. To induce asymmetry in the proposed processes, a Brønsted acid will be used to catalyze a stereoselective cyclization reaction, with a focus on the use of commercially available chiral phosphoric acids. We hypothesize that the chiral phosphoric acid will complex with the starting hydroxy and amino esters and nitriles to initiate a cyclization reaction that preferentially generates one product enantiomer over the other. Our methods rapidly build complex molecules under mild conditions, and our research will result in a significant advance over current state of the art. Preliminary results support the validity of our approach and we will offer insight into the potential uses of the generated products. The ring structures we will prepare are ideal candidates for further manipulation into other biologically relevant structures or for diversification and evaluation themselves. Notably, these investigations will be advanced primarily by M.S. and undergraduate student researchers.