Chemical methods for the synthesis of complex molecules

The National Institute of General Medical Sciences awarded the University of Delaware $479,532 on August 26, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop chemical methods for the synthesis of complex nitrogen-containing small molecules essential to modern pharmaceuticals.

The award funds research on electrophilic nitrogen chemistry to create new synthetic methods that rapidly prepare structurally and topologically complex organic molecules. The project will develop Heck-like reactions of electrophilic nitrogen centers to access sterically congested, stereogenic nitrogen heterocycles in high demand for drug development, and continue work on aza-Heck cyclization and C-alkylation of nitroalkanes to generate complex nitrogen-rich precursors. These advances aim to enable more selective and potent pharmaceuticals with fewer side effects while targeting complex diseases.

Work is performed in Newark, Delaware, with a period of performance through July 31, 2031. The assistance type is a Project Grant.

Abstract

Nitrogen-rich small molecules are essential components of modern medicines, and therefore critical to human health. As medical science has evolved, there has been a drive to develop more selective and potent pharmaceuticals that impart fewer side-effects while simultaneously tackling more complex diseases. At a molecular level, this has resulted in the need to rapidly access more structurally and topologically complex molecules that are able to differentiate between similar biological targets to effect the desired phycological response without unwanted side effects. These challenges continue to drive the need for more efficient synthetic methods to prepare complex nitrogen-containing small molecules. Historically, due to the high electronegativity of the nitrogen atom, small molecule nitrogen chemistry has largely focused on nucleophilic nitrogen centers. However, in recent years, there has been a growing realization that electrophilic nitrogen centers can be easily accessed, and that the reactivity of electrophilic nitrogen provides unique opportunities in the synthesis of complex nitrogen-containing molecules. Our group has contributed significantly to this shifting paradigm, particularly in the areas of AZA-heck cyclization to build complex, stereogenic nitrogen heterocycles and in developing chemistry to effect the c-alkylation of nitroalkanes to access complex nitroalkanes as advanced precursors to nitrogen-rich molecules. Manipulation of high-valent, electrophilic nitrogen centers is at the core of both of these research areas. In this program, we will continue to build on our significant track-record in electrophilic nitrogen chemistry to develop new methods to rapidly prepare complex organic molecules. Specifically, we will develop new heck-like reactions of electrophilic nitrogen centers to access sterically congested, stereogenic nitrogen heterocycles, which are in high demand in modern medicinal chemistry but are challenging to prepare by other means. We will further investigate the mechanism of AZA-heck cyclization to discover how these reactions proceed, and use that understanding to further expand the synthetic horizons of this chemistry. Additionally, we will learn to control absolute stereochemistry in these cyclizations to selectively prepare single enantiomers of these complex molecules. To demonstrate the importance of AZA-heck cyclizations, we will also rapidly prepare several highly complex natural products with significant reported biological activity. Through collaboration, our synthetic efforts will enable biological follow-up studies to probe the modes of action of those compounds. Finally, using our recent discoveries in alkylation chemistry, we will pursue new synthetic methods to prepare and utilize complex nitroalkanes in the synthesis of medically relevant compounds. Overall, we expect that the development of this chemistry will positively impact human health by providing synthetic, medicinal, and process chemists valuable new tools for the construction of nitrogen-rich bioactive small molecules.