Harnessing continuous flow chemistry as a synthetic, biological, and educational tool

Abstract

Flow chemistry has become an increasingly popular solution for addressing common issues in organic chemistry. In many instances, flow chemistry methods can contribute greatly to safer work conditions, reaction scalability, selectivity, space efficiency, and ease of optimization. These benefits of flow chemistry were harnessed in efforts towards cyathane diterpenoid-inspired scaffolds for investigations on these fragments’ potential as therapeutic agents toward the treatment of neurodegenerative diseases, including Alzheimer’s. A proposed intramolecular Buchner ring expansion utilizing largely unexplored, highly reactive diazoalkanes was investigated for the direct formation of [7,6]-bicyclic cyathane diterpenoid fragments. However, after comprehensive investigation, this reaction’s major products were observed to be benzylic C-H insertion and dimerization. Leveraging this newfound C-H insertion reactivity, a continuous flow process for the formation of cyclization products using a cobalt-porphyrin catalyst has been developed. By forming the diazo species in situ using flow chemistry, non-stabilized diazo compounds can be formed safely and efficiently. Resultantly, this platform has been fruitful in the synthesis of cyclopentane-containing bicycles. Beyond organic synthesis, flow methodologies can be equally powerful tools in biology. Currently, high-throughput approaches for determining RNA tertiary structure are lacking; hydroxyl radical cleavage is one example of well-established methods for RNA tertiary structure determination, however, this method is limited with respect to analytical throughput. A flow platform has been developed to address this shortcoming. This method enables for hydroxyl radical cleavage, “catch-and-release” of the aldehydes formed using a novel biotin-hydrazide probe, and reduction allowing for rapid isolation, purification, and analysis of RNA fragments. Finally, attitudes in science education have recently shifted to emphasize current research incorporation into the classroom. To this end, a flow chemistry experiment for pyrrole synthesis was developed to introduce students to modern research methods and technology; conveniently, this same flow platform can be used to synthesize the active pharmaceutical ingredient, Aloracetam. Likewise, learning tools were developed to bridge students’ understanding of chemistry and medicine.