Strategies and Methods for the Synthesis of Aromatic Molecules

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Aromatic molecules constitute 80% of marketed drugs and increasingly are components of new materials, eg sensors and smartphone batteries. Invention and development of new methodology for construction of aromatic compounds based on directed ortho metalation (DoM) reaction has been a central theme of our research. DoM has overtaken traditional electrophilic substitution as the principal means for making substituted aromatic rings and the technology, alone or aligned with transition metal-catalyzed chemistry, has been transferred to the synthesis of commercial drugs. Our research will focus on 1. Metalation Routes to Polysubstituted a-Naphthols and Dihydrobenzofurans. These protocols aim to supercede traditional routes and establish new general methods for the construction of a-naphthols, bioactive natural products, and a class of ligands. 2. DoM-DMG Dance in the Synthesis of Heteroaromatics. This project develops new functional group migration (`dance') reactions for the construction of valuable classes of pharmaceutically relevant heterocycles, overcoming lengthy routes. 3. Photoredox Reactions of DMG-bearing Aromatics. The project aims to discover and develop photoredox-catalyzed reactions to complement or supercede our DoM chemistry. 4. DoM-Kulinkovich Reaction link. The project aims to develop a new general route to optically-active cyclopropanols and to discover a Kulinkovich reaction on DoM-derived aromatic molecules of pharmaceutical value. 5. DoM for Azaborinine Synthesis. Molecules of Project 2 will provide precursors for the synthesis of a new class of B-N heterocycles that have distinct properties of future value for organic electronic and sensing materials. 6. Total Synthesis of Natural Products. The project concerns the total synthesis of several bioactive natural products, e.g. alkaloids, aromatic polyketides). The syntheses will showcase our DoM and DreM strategies of broad applicability. 7. Biaryl Atropisomerism. Biaryl atropisomers are molecules that are optically active by virtue of restricted rotation about the central aryl-aryl bond. We aim to synthesize and correlate experimental-computational rotational barriers of simple and macrocyclic biaryls, molecules that are of current interest in drug discovery programs. 8. Amide DMG-directed Ir-catalyzed C-H Bond Activation/Borylative Coupling. In this project, the scope/limitations of the reaction and the orthogonal C-H activation-Suzuki-Miyaura process will be studied. The requested funding will support research activity of 7 MSc, 3 PhD, 10 undergrads, and several visiting grad students (Australia, France, Germany, and Spain).