GOALI: Taming Ambident Reactivity in the Alkylations of Pharmaceutically Relevant N,O-Heterocycles via Catalysis

With support of the Chemical Catalysis program in the Division of Chemistry, Professor Doug E. Frantz of the University of Texas at San Antonio (UTSA) and Eric Simmons and Albert DelMonte in the Chemical Process Group at Bristol Myers Squibb (BMS) are investigating new chemical reactions to improve the efficiency and sustainability of manufacturing routes towards pharmaceuticals on industrial scale. To achieve this goal, this academic-industrial collaboration will focus on the discovery, design, and development of new metal-based catalysts to precisely control either carbon-oxygen or carbon-nitrogen bond formation in pharmaceutically relevant molecular scaffolds. Both carbon-oxygen and carbon-nitrogen bonds are highly prevalent in pharmaceutical drug substances. Unfortunately, in many cases, selective formation of a carbon-oxygen bond over a carbon-nitrogen bond, for example, remains a formidable challenge in the pharmaceutical industry as catalytic synthetic methods that can tame this promiscuous behavior in compounds that contain proximal oxygen and nitrogen atoms are lacking. The Frantz-BMS team will utilize a combination of state-of-the-art high-throughput experimentation techniques along with quantitative reaction optimization and detailed computational studies to identify and rationally optimize catalytic systems that can dictate the formation of carbon-oxygen or carbon-nitrogen bonds in pharmaceuticals and synthetic intermediates. These efforts will not only reduce the cost and environmental impact of manufacturing routes to life-saving drugs in the pharmaceutical industry but will also broaden the scope of new catalytic technologies suitable for large-scale chemical syntheses in the agrochemical and fine-chemical industries as well. The broader impacts of the award also encompass multiple activities that focus on enhancing the educational and professional development of all participants in the award. Students participating in this research at UTSA will benefit from a unique training experience through a recurring annual 3-week summer sabbatical program at the BMS New Brunswick site in New Jersey. During this time, students will gain firsthand experience industrial techniques to accelerate reaction discovery with cutting-edge instrumentation that is usually untenable in most academic research environments. In addition, BMS scientists will conduct annual workshops to engage the entire Department of Chemistry at UTSA on the latest technologies and approaches that are implemented to accelerate reaction discovery in the pharmaceutical industry.

Ambident reactivity is a fundamental concept in organic chemistry, yet significant gaps persist in our understanding of the controlling elements that dictate chemoselectivity in these systems. As a result, retrosynthetic strategies towards molecular targets often avoid ambident substrates as reliable, predictable, and robust catalytic methods using these reagents are lacking. On an industrial scale, these indirect synthetic routes that circumvent the utility of ambident nucleophiles ultimately raise the cost of goods in the pharmaceutical, agrochemical, and fine chemical industries. Nowhere is this issue more prevalent than in pharmaceutically relevant N,O-heterocyclic systems that are notorious ambident nucleophiles in alkylation reactions that lead to competing and uncontrollable C-O and C-N bond formation. In response, this funded research will invent and implement new catalytic methods that can deliver predictable catalytic control of ambident reactivity in N,O-heterocycles to shorten research and development timelines for bringing new drugs to market and accelerate basic scientific discoveries in academia. Importantly, the new catalyst systems developed will also open the door to the utilization of non-traditional alkylating agents that obviate the use of genotoxic alkyl halides. The funded research combines the power of high-throughput experimentation (HTE) available at BMS with the expertise in mechanistic analysis at UTSA to accelerate the discovery of new catalytic systems capable of dictating chemoselective alkylations on a wide range of pharmaceutically relevant N,O-heterocycles.

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.

Award Number: 2538329
Principal Investigator: Douglas Frantz
Funds Obligated: $532,000
State: MO