Version 2 2022-12-30, 17:05Version 2 2022-12-30, 17:05
Version 1 2022-12-15, 17:03Version 1 2022-12-15, 17:03
journal contribution
posted on 2022-12-30, 17:05authored byIrini Abdiaj, Santiago Cañellas, Alejandro Dieguez, Maria Lourdes Linares, Brenda Pijper, Alberto Fontana, Raquel Rodriguez, Andres Trabanco, Eduardo Palao, Jesus Alcázar
Herein, we report an end-to-end process including synthesis,
work-up,
purification, and post-purification with minimal human intervention
using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol
are twofold. First, the automated sequential generation of organozinc
reagents from readily available alkyl halides offers a large diversity
of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second,
a fully automated liquid–liquid extraction has been developed
and successfully applied for unattended operations. The workflow was
completed with mass-triggered preparative high-performance liquid
chromatography HPLC, providing an efficient production line of compounds
with enriched sp3 character and better drug-like properties.
The modular nature allows a smooth adaptation to a wide variety of
synthetic methods and protocols and makes it applicable to any medchem
laboratory.