The Development of Unorthodox Amine-Acid Coupling Reactions and Their Applications Towards Complex Molecules for a Systems Approach to Chemistry

Abstract

A molecule’s properties are intimately linked to its medicinal function, yet there is a gap in our understanding of the interaction between properties and chemical synthesis. The most popular reaction in medicinal chemistry, the amide coupling, is an ideal arena to explore the relationship of reactions to properties, and ultimately function. Amines and carboxylic acids are among the most abundant materials available for organic synthesis. They are traditionally coupled together using the amide coupling. This is due to the robustness of the reaction as well as challenges associated with generating reactive species from these stable functionalities. Theoretically there are many unique ways in which these two plentiful materials can be combined with each of them generating products with diverse properties. Indeed, there has been a heavy focus recently on developing methodologies to use these pervasive molecules as partners for cross coupling reactions. Our lab is interested in further exploring and developing unique reactivities of amines and acids to complement the amide coupling and using them to explore the complex interplay between physicochemical properties and biological function. By activating the amine as its pyridinium salt and using robotics and high throughput experimentation (HTE), we have developed a selective, deaminative esterification that generates a molecule geometrically identical to the amide but contains one fewer hydrogen bond donor. Mechanistic investigations revealed this reaction proceeds through an alkyl halide intermediate that can be isolated in a one pot manner from the free amine. We have capitalized on this intermediate to synthesize halides and phenolic ethers from amines. To achieve the corresponding amine–acid etherification, we have leveraged HTE to develop an in-situ¬ reduction extension to our esterification protocol. These reactions and several others have been applied to an amine–acid pair to synthesize a series of proteolysis targeting chimeras (PROTACs) as well as fluorescent dyes. These series span a wide range of partition coefficient, charge, and polar surface area while maintaining bulk similarity (and molecular weight) to the “traditional” molecule one would synthesize from amine and acid. We confirm that these subtle structural changes realized by subjecting the same building blocks to varying reaction conditions have a profound effect on the biological activity of the newly synthesized molecules. This dissertation will explore the interplay between these effects through the lens of amine–acid coupling reactions as well as discuss the teaching of new techniques that will enable this understanding.