New Catalysis and Continuous Flow Strategies Toward the Synthesis of Compounds of Interest in Medicinal Chemistry and Materials Science

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Chemical synthesis plays a critical role in the development of fields such as the medicinal and the materials sciences. The present proposal describes new synthetic strategies to access molecules that can significantly impact medicinal chemistry (macrocycles) and materials science (helically chiral aromatics), but suffer from a lack of efficient synthetic methods for their preparation. The proposal addresses the longstanding synthetic challenges associated with each of the classes of compounds. In particular, new forms of catalysis and continuous flow technology will be developed. For the synthesis of macrocycles, the development of new catalytic methods to generate diversely functionalized skeletons is a limiting factor in the exploration of new properties of macrocycles. Our proposal describes the development of novel annulations reactions of diynes, an underexplored functional group in organic chemistry, in macrocyclization chemistry. The annulations allow for the rapid introduction of heterocycles into macrocyclic frameworks. Through exploiting macrocyclization technology in continuous flow, large quantities of macrocyclic frameworks can be formed early in a synthetic route at high concentrations. The new macrocycles with embedded heterocycles can be further functionalized using established protocols to afford diverse unique macrocyclic structures. The second aspect of the proposal concerns the synthesis of helically chiral carbon based materials, or helicenes, which have found numerous applications in chemical sciences. Unfortunately, the exploration of higher derivatives is limited by the traditional UV light mediated methods developed over 40 years ago. The proposal describes a combination of visible light-mediated photoredox strategies and continuous flow techniques to improve the synthesis of smaller helicenes while allowing access to higher carbo- and heterohelicenes. The synthesis of new sensitizer structures based on earth-abundant metals, or organic chiral sensitizers for enantioselective catalysis is motivated by the need to develop “greener” synthetic processes. The application of flow technologies significantly accelerates photochemical processes and will allow gram-scale syntheses of the target compounds for the first time. Altogether, the fundamental research in molecular synthesis described in the present proposal aims to provide methods which are ever more energy efficient, environmentally friendly, safe and produce less waste. While the methods proposed would allow access to interesting and important molecular structures, the catalysis and continuous flow techniques would also have application for a wide variety of compound classes. Consequently, the proposed research should have a significant impact and form HQP that are trained in state-of-the-art synthetic techniques.