Flow and photochemistry as enabling technologies for early-stage drug discovery

The discovery of new therapeutics requires efficient strategies to explore chemical space and rapidly identify bioactive molecules. This thesis investigates the integration of photochemistry and flow chemistry as enabling technologies for early-stage drug discovery, with a particular focus on expanding the toolbox of DNA-encoded chemical libraries (DECLs) and developing scalable synthetic methodologies.
First, a photocatalyzed C–N coupling on DNA is reported, representing the first example of an amidine arylation performed under photoredox conditions directly on DNA. While demonstrating feasibility and robustness, this study highlights current limitations in reaction generality for DECL applications. Building on this, a dual nickel/photoredox catalytic system for amidine arylation in small molecules is developed. Mechanistic investigations reveal the key role of an in situ generated triazine co-catalyst operating through an oxidative quenching cycle, enabling enhanced reactivity, broader nucleophile scope, and improved kinetics. The translation to continuous flow conditions further enhances scalability and productivity.
To address the need for novel bifunctional building blocks, a photoinduced Negishi coupling strategy is introduced for the synthesis of α-heteroaryl-α-amino esters, providing valuable scaffolds compatible with on-DNA chemistry. Finally, a hydrogen atom transfer (HAT) approach using glyoxylate-derived sulfonyl hydrazones enables the conversion of simple alcohols into Reformatsky-type β-hydroxy esters under mild conditions, offering a sustainable alternative to classical methods.
Overall, this work demonstrates how the merger of photochemistry and flow chemistry can expand synthetic capabilities, improve sustainability, and accelerate the development of drug-relevant molecules.