Dearomative Functionalization with Arenophiles

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PROJECT SUMMARY The objective of the work of the parent grant 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. We strive 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. 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. We have prepared a series of potent anticancer natural products and antibiotics and are currently preparing analogues for SAR studies as well as designing prodrugs with improved pharmacokinetics properties. The instrument, UHPLC-MS, to be purchased by funds from this Supplement will allow us for analysis of these highly polar compounds and will greatly facilitate these studies.