Utility and Application of Unsaturated Acylammonium Salts in Organic Synthesis

Baylor University, Waco TX

Investigators

Abstract

With this award, funded by the Chemical Synthesis Program of the Chemistry Division, Prof. Daniel Romo of Baylor University is developing "cascade" reactions that occur sequentially and rapidly build up structural complexity in organic molecules. As co-PI, Professor Dean Tanillo of the University of California, Davis, is studying the mechanistic details that provide for selectivity in the reactions developed in the Romo lab. Modern day organic synthesis research seeks to develop reaction processes that generate multiple carbon-carbon, carbon-oxygen, and carbon-nitrogen bonds in a single operation, and with control of the 3-dimensionnal arrangement of atoms around carbon. This approach significantly increases the efficiency of the synthesis of a variety of molecules, including bioactive natural products and compounds of pharmaceutical interest, and provides access to molecular architectures not previously accessible. In this project, Dr. Romo is utilizing small organic molecules that serve as catalysts to activate substrates leading to initiation of various types of bond constructions with high selectivity. He is exploring a new activation mode that is already proving broadly useful for the development of novel cascade reactions, and greatly impacting efficiency in organic synthesis. Undergraduates working in the research group and in particular those associated with the "Baylor Undergraduate MiniPharma Program" that he initiated, are gaining teamwork and leadership experience, a taste of various aspects of chemical research relevant to the pharmaceutical industry, new research skills, and experience with state-of-the-art equipment, ultimately contributing to publishable research. Prof. Romo is pursuing a novel and broad design principle for organic synthesis based on readily generated chiral unsaturated acylammonium salts, significantly impacting the growing field of scalable, asymmetric organocatalysis. The organocascade processes he is studying include tandem reactions typically initiated by Michael additions (with carbon, nitrogen, and sulfur nucleophiles) that lead to highly practical, enantioselective synthetic routes to carbocycles and heterocycles commonly found in bioactive natural products and pharmaceuticals. Given the importance for organocascade catalysis, mechanistic studies of the various unsaturated acylammonium salt intermediates accessed in this research will be undertaken in collaboration with Prof. Tantillo. These collaborative studies are providing a greater understanding of the mode of activation and enantioselectivity observed with these chiral intermediates. The utility of the developed synthetic methods is being demonstrated by targeting natural products bearing beta-lactones. These in turn serve as proteomics probes with appropriate reporter tags for fundamental studies at the chemistry/biology interface with Prof. Stephan Sieber (Tech Univ of Munich, Germany). The Baylor Undergraduate MiniPharma Program enables undergraduates to get a 'taste' of the pharmaceutical industry by designing, synthesizing, and testing novel derivatives toward a common goal of identifying lead compounds for potential cancer treatment, including glioblastoma. 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.