Dearomative Functionalization with Arenophiles

PROJECT SUMMARY Small, heteroatom-containing complex molecules are common motifs of biological relevance and are highly desired in medicinal chemistry, but they are also often difficult to access. Selective transformations of aromatic compounds could provide a more direct route to such desirable targets; however, the many challenges associated with dearomative functionalization have left these types of reactions widely underdeveloped. The proposed research strives to address this need by bridging the gap between dearomatization and alkene-type chemistry. Fundamentally, the goal of this proposal is to access desirable structural motifs from simple aromatic compounds by developing dearomative functionalizations using small molecules – arenophiles – that formally enable olefin-like reactions on arene substrates. Specifically, in this proposal, we describe several dearomative approaches on non-activated arenes based on catalytic 1,2- and 1,4-difunctionalizations as well as annulations. These transformations will provide unique disconnections and open new horizons for the preparation of complex small molecules. For example, we have made good progress in bottom-up chemical synthesis of 2-DOS aminoglycoside antibiotics using enantioselective 1,2-hydroamination of simple benzene. This strategy will serve the preparation and study of a library of aminoglycosides that are modified at the aminocyclitol core, and grant access to other less-explored derivatives, such as 2-DOF-based antibiotics. Moreover, we propose an extension of arenophile-based dearomatizations to heteroaromatic substrates. Compelling preliminary data demonstrate that several well-established olefin reactions, such as dihydroxylation, reduction, and epoxidation, can now be translated into dearomative functionalization of pyridines. Additionally, transition-metal-catalyzed processes involving pyridine-arenophile adducts will enable a rapid synthesis of a diverse range of functionalized heterocyclic compounds. While traditional approaches to directly functionalize (hetero)aromatic compounds provide limited functionalization options and are hampered by overreaction or decomposition, the arenophile- based strategy permits the selective and controlled introduction of a variety of functional complexity. Finally, this approach provides products that are both challenging to synthesize via existing methods and are complementary to those acquired through chemical or biological dearomative processes. Overall, the development of a general dearomative functionalization platform with arenophiles has the potential to make a profound impact on the pharmaceutical, agricultural, and materials sciences by providing expedient access to complex small molecules with tailored properties from simple and readily available arenes.