High Throughput Experimentation Facilitated Development of Amine-Acid Cross Coupling Reactions

Abstract

High throughput experimentation (HTE) is an important technique which can expedite the hit-to-lead process in drug discovery. The first chapter of this thesis reviews reported applications using HTE in medicinal chemistry research and provids the basics of establishing HTE capabilities including software, hardware, and data analysis. We have demonstrated the establishment of an HTE platform in our lab. HTE could leverage areas like machine learning, cheminformatics, and reaction prediction. With an interest in bridging these areas, we have reported an algorithm to map chemical space of amine–acid coupling system, which utilizes two of the most significant building blocks for medicinal chemists. The scientific rationale in connecting amine–acid coupling with physicochemical properties is discussed in Chapter 2. With the interest in developing novel methodologies for amine–acid coupling, and to showcase the HTE capabilities we established, we have identified a unique amine–acid C–O bond formation applying carboxylic acids and arenediazonium salts as an activated form of anilines. Chapter 3 discusses the development of this copper catalyzed amine–acid C–O esterification and discusses in detail ultraHTE screening, where reactions are performed in 1,536 wellplates, for the miniaturized general substrate scope investigation. To push beyond C–O bond formation with an aim of expanding amine–acid coupling system, we also explored metallaphotoredox catalysis for deaminative–decarboxylative C–C bond formation. In Chapter 4, the discovery and optimization of the novel method to couple redox active esters (NHPI esters) with triazenes are discussed. The unique substrate pairs also showed the possibility to form decarboxylative–deaminative coupling products and decarboxylative amination products, which again, showcased the strong connection between transformation and properties. This work, as a whole, demonstrates the significance of HTE in the search for novel reactivity, and demonstrates the significance of the amine–acid coupling system, evidenced by developing amine–acid C–O, C–C, and C–N bond formation.