Regio- and enantioselective electrophilic aromatic substitution on drug-like molecules

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The Chemical Catalysis Program of the Chemistry Division supports the project by Professor Gustafson. Professor Gustafson is a faculty member in the Department of Chemistry at San Diego State University. He is developing new classes of catalysts for electrophilic aromatic substitution. The goal of this research program is to design new catalysts that allow for the direct functionalization of both simple and complex aromatic molecules, including pharmaceuticals and proteins. Lewis basic groups are capable of activating electrophiles and are readily incorporated into catalyst structures, allowing for modular catalyst design. The project lies at the interface of catalytic, synthetic and physical organic chemistry. Therefore, it is well suited for the education of scientists at all levels. Professor Gustafson's group is well positioned to provide the highest level of education and training for students underrepresented in science due to San Diego State University's unique and diverse student population. Outreach activities involving underrepresented students at community colleges are part of the project. Lewis bases can catalytically activate diverse electrophiles towards electrophilic addition reactions. The Gustafson group has recently demonstrated that Lewis bases such as thioureas and phosphine sulfides can catalyze the halogenation or sulfenylation of aromatic feedstocks under very mild conditions. Preliminary mechanistic studies suggest this chemistry proceeds through a covalent halenium-catalyst adduct, and that the structure of the catalyst can influence the reaction outcome. The proposed research involves both in-depth mechanistic studies and the development of new catalysts to extend the project to more complex systems. There are three major questions this proposal strives to answer: How do Lewis base catalysts control the regioselectivity of phenol chlorination, and can this selectivity be extended to other classes of arenes? Second, how do Lewis bases conjugated to Bronsted acids catalyze the mild sulfenylation of heterocycles, and can this reaction be extended to peptides, proteins, and natural products? Furthermore, can changes in the Lewis base lead to chemoselectivity towards other classes of arenes? Finally, can chiral Lewis base catalysts be designed to effect enantioselective halogenation and sulfenylation? The educational plan includes outreach to underrepresented students at local community colleges to introduce them to research opportunities available to undergraduates. This outreach activity includes hands-on presentations at local community colleges that introduce students to computational chemistry in the context of the conformational analysis of butane.