Utility and Application of Unsaturated Acylammonium Salts

Baylor University, Waco TX

Investigators

Abstract

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Daniel Romo of Baylor University is studying the development of reaction processes that generate carbon-carbon and carbon-heteroatom bonds in a single operation. These methods will significantly increase the efficiency of bioactive natural product and pharmaceutical synthesis. In the proposed research, the development of complex cascade or domino reactions are targeted that build up structurally complexity very rapidly. Organocatalysis involves the use of small, chiral organic molecules to activate substrates and initiate various bond constructions. Despite recent advances in covalent organocatalysts, there is a paucity of general substrate activation modes, with only limited types revealing multiple reactive sites in a single catalytic cycle. This research, in collaboration with a computational chemist, will continue exploration of a novel activation mode that is already proving broadly useful for the development of novel organo-cascade reactions that greatly impacts efficiency in organic synthesis. In addition, the methods being developed are expected to enable biological studies of complex naturally-occurring compounds with potential activity as anticancer and antibiotic agents. Undergraduate students, in particular those associated with the Baylor Undergraduate MiniPharma Program, working on these projects are gaining teamwork and leadership experience, a taste of various aspects of pharmaceutical research, new specialized research skills, and experience with state-of-the-art equipment. In addition, the Baylor University Advanced Instrumentation workshop provides an opportunity for faculty and students from local primarily undergraduate institutions to visit Baylor University to gain hands-on experience with these advanced synthetic methods and state-of-the-art equipment. Through this award, Professor Daniel Romo from Baylor University is pursuing a novel and broad design principle based on readily generated chiral unsaturated acylammonium ions, adding an important foray into the growing field of scalable, asymmetric organocatalysis. The organo-cascade processes to be studied include the development of (i) a dynamic kinetic resolution involving a previously described Diels-Alder-lactonization cascade and (ii) a Giese-type radical-initiated cyclization. These approaches have the potential to provide new, practical, enantioselective synthetic routes into both carbocycles and heterocycles commonly found in bioactive natural products. Mechanistic studies of the reactions of the chiral unsaturated acylammonium salts will be undertaken in collaboration with Professor Dean Tantillo (UC Davis). It is anticipated that these collaborative studies will provide insight into mechanistic pathways and problematic substrates and provide a greater understanding of the mode of activation and of enantioselection observed in these reactions. The methods being developed will be applied to the stereocontrolled synthesis of natural products including beta-lactone natural products with great potential for structure-activity relationship studies. In particular, several of these are being targeted as proteomic probes in a chemical biology collaboration with Professor Stephan Sieber of the Technical University of Munich, Germany. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.