New Amine-Acid Couplings and Their Impact on Medicinal Properties

Project Summary. A new molecular product becomes real when chemical building blocks are united with a chemical reaction. The status quo in drug discovery is to acquire a large number of building blocks and stitch them together using a small number of reactions. Common building block pairs are classically matched to reactions through pattern recognition - the amide coupling is used for amines and carboxylic acids, the Suzuki coupling is used for bromides and boronates.

In this established paradigm, building blocks are the source of diversity. The success of this classic approach relies on the commercial availability of the building blocks, and best introduces diversity around the periphery of the molecule. Here, we explore a new paradigm, where a small number of building blocks are stitched together using a large number of reactions. In this new paradigm, the reacting atoms are the source of diversity, complementing the classic approach.

In the classic approach, an amine and carboxylic acid building block would be united by the amide coupling. We explore the theoretical and experimental development of amine-acid coupling reactions that are distinct from the amide coupling. We focus on new amine-acid coupling reactions that forge carbon-carbon bonds. The popularity of C-C bonds in pharmaceuticals and natural products suggests a necessity for new C-C bond-forming reactions.

A key innovation is the use of chemoinformatics to demonstrate that amines and acids are available in high chemical diversity, typically more cost effective than organometal and organohalide building blocks and generally safe and stable to handle. Leveraging high-throughput experimentation to identify specific combinations of catalysts and ligands, we find that we are able to discover amine-acid C-C coupling reactions. The advent of our new amine­ acid C-C coupling reactions allows for building block repurposing of the two most abundantly available building blocks - amines and acids - for the synthesis of the most popular atom arrangements - C-C bonds - found in drugs. Achieving these novel amine-acid C-C couplings requires identification and optimization of new catalyst and reagent systems that enable broad substrate scope, user-friendliness, and potentially introduction of asymmetry.

Using modern high-throughput techniques, we search for such reaction conditions in the hopes of inventing new and impactful amine-acid coupling reactions. While C-C bonds are an area of focus, other complexity generating reactions are also considered, along with amine-acid C-N and C-O couplings. We showcase the significance of our approach in drug discovery through the late-stage diversification of complex pharmaceuticals, and through the synthesis of diverse chemical libraries.

Grant Number: 5R01GM144471-04
NIH Institute/Center: NIH
Principal Investigator: Timothy Cernak