High-throughput experimentation enabled late-stage functionalization as a tool for sustainable chemistry

Abstract: Late-stage functionalization (LSF) is transforming pharmaceutical discovery by enabling direct, selective modification of complex drug-like molecules without rebuilding core scaffolds. This presentation will describe the work we have done at AstraZeneca over the last 6 years integrating high-throughput experimentation (HTE) with late-stage C–H functionalization to create a practical, sustainability-forward engine for analogue generation, accelerating SAR while reducing material use, solvent demand, and waste. In drug discovery, LSF unlocks efficient diversification pathways for complex drug molecules through targeted activation of unfunctionalized C–H bonds in advanced intermediates. By avoiding lengthy de novo synthesis and eliminating the need for pre-installed reactive handles, this strategy enables precise molecular editing to enhance analogue potency, refine physicochemical/ADME properties, and expedite installation of chemical probes. From a green chemistry standpoint, LSF can reduce dramatically step count, including protecting-group manipulations, redox adjustments, and convergence detours that amplify material and energy demands. Fewer steps translate into lower process mass intensity (PMI) through reduced solvent volumes, excess reagent, byproduct formation, and purification burdens per kilogram of product. Five HTE-enabled LSF platforms will be described that expand selectivity and scope while embedding green chemistry principles (i.e. safer solvents and auxiliaries, catalysis, energy efficiency, and waste prevention). Collectively, this work establishes HTE-LSF as a paradigm where accelerated molecular innovation converges with environmental responsibility, proving that efficiency and sustainability are synergistic drivers in pharmaceutical research.