Acoustic Droplet Ejection Enabled Automated Reaction Scouting

Abstract

Miniaturization and acceleration of synthetic chemistry are critically important for rapid property optimization in pharmaceutical, agrochemical, and materials research and development. However, in most laboratories organic synthesis is still performed on a slow, sequential, and material-consuming scale and not validated for multiple substrate combinations. Herein, we introduce fast and touchless acoustic droplet ejection (ADE) technology into small-molecule chemistry to transfer building blocks by nL droplets and to scout a newly designed isoquinoline synthesis. With each compound in a discrete well, 384 random derivatives were synthesized in an automated fashion, and their quality was monitored by SFC-MS and TLC-UV-MS analysis. We exemplify a pipeline of fast and efficient nmol scouting to mmol- and mol-scale synthesis for the discovery of a useful novel reaction with great scope.

Multicomponent reaction–derived covalent inhibitor space

“…Nanoscale synthesis not only allows for fast and automated production of large compound collections but also is highly sustainable as much fewer valuable reagents, solvent, and consumables are used ( 55 ). We have recently introduced acoustic droplet ejection (ADE) as a suitable tool for the automated nanoscale synthesis of libraries of small molecules ( 40 , 48 , 54 ). Here, we describe the Ugi-4CR of carboxylic acids, primary amines, formaldehyde, and N -(2-isocyanoethyl)acrylamide 22 as an example for the nanoscale synthesis of electrophiles for potential covalent biological space scouting.…”

Sustainability by design: automated nanoscale 2,3,4-trisubstituted quinazoline diversity

“…Recently we reported nanoscale synthesis of libraries of different scaffolds using acoustic dispensing ejection technology (ADE). [16][17][18] A disadvantage of ADE is the limited solvent compatibility which somehow restricts organic chemical reactions. Currently, only solvents are compatible with a rather high boiling point and a low volatility such as DMSO, water, ethylene glycol and similar solvents.…”

Isocyanide 2.0

“…In our laboratory, the access to a large number of isocyanides with high structural diversity is crucial for example to explore the structure-activity relationship (SAR) and to prepare large libraries of IMCRs on a nanoscale or in the DEL format. [38][39][40][41][42] Thus, we revisited the formamide to isocyanide dehydration and came up with a completely revised procedure avoiding any type of aqueous workup. The advantages of our very general isocyanide syntheses are increased synthesis speeds and thus decreased exposure of the chemist to badly smelling fumes, very mild conditions giving access to hitherto unknown classes of isocyanides, rapid access to large numbers of functionalized isocyanides, increased yields, high purity, exemplified scalability over 5 orders of magnitude, and less reaction waste resulting in a highly reduced environmental footprint.…”