The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis

• DOI: 10.1021/acs.accounts.7b00428
• Publication Date: 2017-11-27T15:21:41Z
• Authors: Shane W. Krska; Daniel A. DiRocco; Spencer D. Dreher; Michael Shevlin
• Keywords: Scope (computer science)

ConspectusThe structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made apply them complex drug intermediates. The use high-throughput experimentation (HTE) techniques offers means overcome this fundamental by facilitating the rational exploration large arrays catalysts and reaction conditions in time- material-efficient manner. Initial forays into HTE our laboratories for solving chemistry problems centered around screening chiral precious-metal homogeneous asymmetric hydrogenation. success these early efforts developing efficient catalytic steps late-stage development programs motivated desire increase scope approach encompass other high-value chemistries. Doing so, however, required advances reactor workflow design automation enable effective assembly agitation heterogeneous mixtures retention volatile solvents under wide range temperatures. Associated innovations analytical greatly increased efficiency reliability methods. These evolved have been utilized extensively develop highly innovative catalysis solutions most challenging large-scale pharmaceutical synthesis. Starting with Pd- Cu-catalyzed cross-coupling chemistry, subsequent expanded valuable synthetic transformations such as phase-transfer catalysis, photoredox C–H functionalization. As experience confidence matured, we envisioned their application beyond process address needs medicinal chemists. Here problem generality is felt acutely, approaches should prove broadly enabling. However, quantities both time starting materials available troubleshooting space generally severely limited. Adapting led us invest smaller predefined transformation-specific “kits” push boundaries miniaturization screening, culminating “nanoscale” carried out 1536-well plates. Grappling also inspired cheminformatics-driven Chemistry Informer Libraries. next-generation promise empower chemists run orders magnitude more experiments “big data” informatics troubleshooting. With advances, poised revolutionize how across industry academia discover new methods, tools broad utility, practical significance.