Aromatic hydrocarbons (arenes) are some of the most elementary feedstock chemicals, produced annually on a million metric ton scale. Chemical transformations of these compounds play a fundamental role in everyday life; for example, in the production of polymers, paints, agrochemicals, and pharmaceuticals. Dearomatization reactions convert simple, readily available arenes into more synthetically useful unsaturated intermediates. Our long term goal is to provide new chemical transformations and strategies that will selectively introduce functionality and, consequently, greatly expand the dearomative chemical toolbox. Small, heteroatom-containing complex molecules are common motifs of biological (as well as pharmaceutical and agrochemical) 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 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 enable reactions of isolated alkenes in an arene substrate. Our preliminary results demonstrate that well-established olefin reactions, such as dihydroxylation and reduction can now be more directly applied to arenes. Additionally, arenophiles, in combination with transition metal catalysis, provide uniquely reactive substrates for nucleophilic substitution reactions, and could enable the rapid synthesis of a diverse range of aminofunctionalized alicyclic compounds. While many known attempts to directly functionalize aromatic compounds result in overreaction or decomposition, this arenophile-based strategy permits selective and controlled introduction of functional complexity. Finally, this approach provides products that are both challenging to synthesize via existing methods and complementary to those acquired through biological or chemical 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.

Public Health Relevance

Reaction strategies that allow for the rapid introduction of complexity have become increasingly important in the areas of drug discovery, agriculture, and materials science. The proposed research will greatly simplify and expand synthetic pathways from simple arenes to molecular motifs that are prevalent in bioactive natural products and pharmaceuticals. The objective of this proposal is to develop new strategies, methods, and reactivity principles to convert aromatic compounds into complex small molecules that are highly desirable but not readily accessible.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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Hernandez, Lucas W; Klöckner, Ulrich; Pospech, Jola et al. (2018) Nickel-Catalyzed Dearomative trans-1,2-Carboamination. J Am Chem Soc 140:4503-4507
Okumura, Mikiko; Shved, Alexander S; Sarlah, David (2017) Palladium-Catalyzed Dearomative syn-1,4-Carboamination. J Am Chem Soc 139:17787-17790
Hernandez, Lucas W; Pospech, Jola; Klöckner, Ulrich et al. (2017) Synthesis of (+)-Pancratistatins via Catalytic Desymmetrization of Benzene. J Am Chem Soc 139:15656-15659
Southgate, Emma H; Holycross, Daniel R; Sarlah, David (2017) Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene. Angew Chem Int Ed Engl 56:15049-15052
Okumura, Mikiko; Nakamata Huynh, Stephanie M; Pospech, Jola et al. (2016) Arenophile-Mediated Dearomative Reduction. Angew Chem Int Ed Engl 55:15910-15914
Southgate, Emma H; Pospech, Jola; Fu, Junkai et al. (2016) Dearomative dihydroxylation with arenophiles. Nat Chem 8:922-8